Kenneth S. Kleinman and Dennis A. Casciato
I. OVERVIEW. Acute renal failure (ARF) syndrome is a constellation of worsening renal function, electrolyte, acid base changes, and changes in fluid and volume status. The three categories of ARF syndrome are prerenal failure, direct renal tubular damage (acute tubular necrosis [ATN], tubulointerstitial nephritis, acute glomerulonephritis), and postrenal failure (obstruction of the renal and urinary collecting system). These syndromes often overlap but are helpful to define diagnostic and therapeutic approaches.
The renal failure may be due to direct or indirect consequences of the tumor, anticancer therapy, immunosuppression, infectious complications, postoperative ARF, or treatments for complications (antibiotics, diagnostic tests, etc.). Furthermore, with improved response and cure rates for cancer patients, residual chronic kidney disease (CKD) is becoming an increasingly common complication of successful cancer treatments.
ARF, especially in the hospitalized patient, is often “multifactorial” and often includes diagnostic tests (contrast agents for CT scans), changing volume status, and nephrotoxic agents. A careful and thorough history, physical examination, and appropriate diagnostic tests including a urinalysis are most helpful for diagnosis, since urine output may decrease and not be available at future times. When ARF occurs in hospitalized patients, review of all physician orders, medication lists, nursing records, vital signs, and surgical records may yield valuable information.
II. PRERENAL FAILURE
A. Pathogenesis. Decreased effective circulating volume (ECV, i.e., from vomiting, diarrhea, blood loss) provides a physiologic stimulus for metabolic and biochemical changes, which lead to reduced renal blood flow and glomerular filtration rate (GFR). The patient with decreased ECV has a baroreceptor-mediated stimulus for increased secretion of antidiuretic hormone (ADH), diminished renal blood flow, and physiologically increased circulating levels of renin, angiotensin II, and aldosterone.
The combined effects of decreased renal blood flow and increased levels of ADH, angiotensin II, and aldosterone result in excretion of a low urine volume that is highly concentrated (elevated urine specific gravity and osmolality), contains little sodium, and often contains large amounts of potassium (the potassium can be variable and is typically not used as a diagnostic test). The body is trying to maintain blood pressure and hemodynamic stability at the expense of renal function. Table 31.1 shows laboratory values that distinguish prerenal failure from renal failure in oliguric patients.
Table 31.1 Distinguishing Prerenal from Renal Causes of Azotemia
FE, Fractional excretion; U, concentration in urine; S, concentration in serum; Na, sodium; creat, creatinine; BUN, blood urea nitrogen.
1. Decreased GFR leads to retention of urea (along with sodium) and creatinine. Reabsorption of filtered urea is increased in the proximal nephron as well as in the distal nephron due to slow tubular flow, a high concentration of urea in tubular fluid, and elevated ADH. Thus, more urea than creatinine is retained, leading to a characteristic elevated blood urea nitrogen (BUN) to serum creatinine ratio.
2. The serum creatinine level is primarily reflective of muscle mass and GFR, when in a “stable state.” Elderly patients and poorly nourished patients with less muscle mass have a relatively low serum creatinine. Because of this, an important clinical pearl/caveat is that serum creatinine levels may still be in the “normal lab range” yet GFR may have dropped significantly.
3. BUN is a metabolic waste product of protein intake, produced within the liver and excreted by the kidney. Although ARF will lead to increases in creatinine and BUN, a lower protein intake and/or diminished liver function, and cachexia with muscle wasting may result in BUN levels that may not be as elevated. Conversely, high protein intake, significant catabolic states, blood in the gastrointestinal tract, and severe prerenal states may result in BUN levels that are dramatically elevated in relation to the serum creatinine.
B. Causes of prerenal failure. Table 31.2 shows general causes of prerenal failure with specific factors that may predispose patients with malignancies to prerenal failure.
Table 31.2 Cause of Decreased Effective Circulating Volume and Prerenal Failure in Patients with Malignancies
C. Diagnosis. The history often reveals likely causes of increased fluid loss (e.g., diarrhea, vomiting, bleeding) or of sequestration (e.g., pleural effusions, ascites, edema, “third spacing,” retroperitoneal hemorrhage, congestive heart failure). Decreased intake of sodium, protein, and fluids may be more difficult to elicit. The physical examination is of paramount importance in assessing volume status and finding clues to the pathogenesis of aberrations, as follows:
1. Hypotension is recognized with a supine systolic blood pressure (BP) of <90 mm Hg. Changes in hemodynamic parameters (orthostatic changes) are recognized by a drop in systolic BP of 20 mm Hg or in diastolic BP of 10 mm Hg and increased heart rate (10 to 20 beats/min) when moving the patient from the supine to sitting or standing positions. These findings are suggestive of intravascular volume depletion and thus low ECV. Medications that affect blood pressure (antihypertensives) and heart rate (beta-blockers and calcium channel blockers) should be taken into account and be associated with more modest changes in these hemodynamic parameters. Early recognition of intravascular volume depletion by careful measurement can prevent later complications.
2. Flat neck veins in the supine position (in patients whose neck veins can be demonstrated by gentle occlusion) suggest volume depletion.
3. In patients without the finding of volume depletion, careful palpation and percussion of the bladder, rectal examination of the prostate of male patients, and pelvic examination in female patients may divert attention to an obstructive cause.
4. Occult prerenal failure may be present that escapes detection by any of the above measures. In such patients, there should always be a high clinical suspicion and consideration of an occult change in cardiac function, which is often from subclinical myocardial infarction, transient or persistent arrhythmias, valvular dysfunction, or myocardial dysfunction related to medications, aortic dissection, or other causes. Acute adrenal insufficiency may develop as a consequence of metastasis to the adrenal or pituitary glands, discontinuance of chronic corticosteroid therapy in the acutely hospitalized patient (for whatever reason), or the requirement for “stress doses” with associated emergency surgery, sepsis, or other reasons. Thus, many clinical scenarios require the careful administration of a fluid challenge and review of the changing clinical status.
5. Loop diuretics given as an intravenous challenge are often used in acutely oliguric patients. An increased urinary output suggests that obstruction is not present and that the renal tubules are functioning. Such response, however, does not clarify or correct the underlying abnormality causing the initial decrease in urine production, and except for overload states such as congestive heart failure. The diuretic may make the prerenal failure worse.
D. Management of prerenal failure is to correct the underlying cause and, when possible, to restore ECV to normal.
1. Hypovolemic patients usually require large volumes of crystalloids (i.e., 0.9% sodium chloride with or without glucose) or colloidal solutions, (i.e., albumin). Plasmanate contains 5% albumin and often requires a larger infused volume, whereas 25% albumin contains 12.5 g of albumin per 25 mL, which is a lesser volume and is preferred in the patient who may have occult volume overload. These solutions also contain significant amounts of sodium. Although albumin solutions specifically increase intravascular volume, they are expensive, and the effect is often transient. Some nephrologists will give an additional trial of an osmotic diuretic such as mannitol, 12.5 to 25 g, either once or twice, to improve the ECV.
2. Obstruction to urinary outflow should be considered in all patients who do not respond to a fluid challenge. In such patients (especially men), insertion of a Foley catheter should be performed. If the problem is still not corrected, all such patients should undergo an imaging procedure to visualize the kidneys and collecting system. Ultrasonography is the safest, most convenient, and available, noninvasive choice and does not require the use of intravenous contrast agents. Computed tomography (CT) scan of the pelvis may also be useful, although intravenous dye may be required; the dye itself can be nephrotoxic, especially in the patient with a low ECV.
3. Reversible renal failure is diagnostic of prerenal failure and often not known until some time after a therapeutic trial and repeat blood and urine testing. If not treated effectively or completely, prerenal failure can lead to more significant kidney damage and ATN. Once established, ATN may be prolonged, more difficult to manage, associated with prolonged hospital stays, and associated with significant morbidity and dramatically increased mortality.
III. POSTRENAL FAILURE: OBSTRUCTIVE UROPATHY
A. Pathogenesis
1. Ureteral obstruction. Uremia may be caused by bilateral obstruction (or unilateral obstruction in the case of a single functioning kidney) as a result of the following:
a. Bladder tumors and tumors of the collecting systems
b. Uterine tumors, especially carcinoma of the cervix
c. Retroperitoneal tumors (rare), including lymphoma, sarcomas, and metastatic tumors
d. Intrinsic renal tumors (rare)
e. Retroperitoneal fibrosis, including that induced by irradiation, drugs (busulfan), carcinoid tumors (especially rectal), Gardner syndrome (intestinal polyposis), or desmoplastic reactions to metastases
f. Blood clots within the collecting system or bladder from bleeding
g. Renal papillary necrosis
h. Nephrolithiasis
i. Stone and/or crystal accumulations from high production or excretion of uric acid
j. Some medications in rare cases may crystallize from supersaturation of the agent and become the primary component of stones. Drugs that induce calculi include magnesium trisilicate, ciprofloxacin, sulfa medications, triamterene, indinavir, and ephedrine (alone or in combination with guaifenesin).
2. Outlet obstruction of the urethra. Causes include primary cancer of the prostate, urethra, cervix, ovary, bladder, or endometrium. Metastases from the lung, gastrointestinal tract, breast, and melanoma to the pelvic organs, prostate, or urethra are rare causes of this complication.
B. Diagnosis
1. Symptoms are often absent or insidious in onset. Anuria is highly suggestive, but partial high-grade obstruction of ureters can occasionally cause renal failure with a normal urine volume. A variable urine output or overflow incontinence causing dribbling (and the strong smell of urine during physical examination) suggests bladder outlet obstruction.
2. Physical findings are those of the underlying disease. Dullness to percussion in the suprapubic region suggests a mass or distended bladder.
3. Ultrasonography may show hydronephrosis. However, acute obstruction or chronic obstruction wherein the collecting system is encased in tumor may show minimal abnormalities. A normal-appearing but full collecting system in an oliguric patient suggests obstruction. Blockage of only one kidney may be less severe. In some cases, ultrasound may miss obstruction, especially when ECV and urine volume are low.
4. Postvoid residual urine determination is often useful in evaluating for outlet obstruction from urethral swelling, stenosis, or scarring; benign prostatic hypertrophy in the male or an ovarian mass in the female patient; or other urologic disease that may be precipitated by medications or not be apparent. A high clinical index of suspicion and brief trial of urethral catheterization (Foley or red Robinson catheter) with significant urine volume and improvement in renal function are gratifying to the patient and clinician alike.
5. Cystoscopy demonstrates bladder outlet obstruction, shows the extent of bladder tumors, and permits retrograde ureterography, which may demonstrate ureteral stenosis or blockage of the ureterovesicular junction. Once again, this procedure can be not only diagnostic but also therapeutic for the cancer patient with renal failure.
C. Management
1. Obstruction of the urinary tract is accompanied by infection and in some cases renal calculi (i.e., struvite/magnesium ammonium phosphate, uric acid stones). Obstruction is a medical emergency requiring immediate diagnosis, treatment, and management. As in prerenal failure, postrenal obstruction, if not corrected, can lead to ARF syndrome and is also a cause of CKD.
2. Stones may pass spontaneously or can be removed by shock lithotripsy or by one of several available urologic procedures.
3. Blood clots in the collecting system will lyse spontaneously; larger clots in the bladder should be removed by continuous bladder irrigation and/or cystoscopy.
4. Retroperitoneal fibrosis may be treated by percutaneous nephrostomies or by surgical release of the involved ureters.
5. Obstructing lymphomas are usually successfully managed with chemotherapy, with or without focal radiation therapy.
6. Solid tumors usually require percutaneous catheter placement under combined ultrasound and fluoroscopic guidance. Stents placed from below are less commonly used. Systemic chemotherapy may be considered for responsive tumors. High-dose pelvic irradiation may be considered as an alternative, as may diverting ureteral surgery. Most patients with pelvic tumors causing obstruction, however, are at an advanced stage of disease; therapy, including percutaneous drainage of the renal pelvis, must be carefully considered in light of the potential for palliation, the extent of disease, and the overall prognosis.
IV. DIRECT RENAL TUBULAR DAMAGE CAUSING RENAL FAILURE
A. Acute renal failure may have an abrupt onset immediately after renal insult (e.g., radiocontrast administration, hyperuricemia after tumor lysis, cholesterol embolization after intravascular procedures). ARF may also arise more insidiously over days to weeks as an indirect consequence of malignancy (e.g., hypercalcemia, myeloma kidney resulting from deposits of Bence-Jones proteins) or therapy (e.g., interstitial nephritis after administration of certain therapeutic agents).
1. Oliguria is often present in more severe and dramatic episodes of ARF; in this case, laboratory parameters in Table 31.1 may be useful in distinguishing it from prerenal failure. Most causes of ARF and many patients with ARF, however, present with normal or nearly normal urine volumes.
2. Oliguria is defined as >400 to 500 mL/24 hours. These “magical numbers” are not arbitrary but rather based upon renal physiology. Since 600 mOsm of solute need to be excreted each day, and the maximal concentrating ability of the kidney is 1,200 mOsm, a minimum of 400 to 500 mL of urine needs to be excreted each day to excrete these solutes. Also called “nonoliguric” renal failure, a normal or higher urinary output in ARF is typically related to less severe renal failure. Despite the reduction in GFR and inability to remove adequate metabolic waste products, kidney tubular cells increase fractional excretion of water and maintain what appears to be a normal urine volume, often fooling the patient and clinical staff into complacency despite a marked reduction in GFR and highly abnormal laboratory markers of renal function.
3. The finding of complete anuria (no urine output) is typically only seen in extreme cases of severe renal failure (renal cortical necrosis, profound ATN, and acute glomerulonephritis) or complete obstruction that affects both kidneys or, in some cases, one anatomic or functional kidney. Anuria leads to more dramatic and quicker changes in electrolyte and fluid complications and requires more immediate management.
4. Although ARF is often transient and reversible, certain causes can result in permanent renal failure (e.g., cisplatin toxicity, mitomycin-induced hemo lytic–uremic syndrome). Drugs may cause injury to the kidney by a variety of mechanisms (Table 31.3). Although ARF may resolve, patients are often left with residual renal dysfunction and CKD.
B. Acute tubular necrosis (ATN) usually has an abrupt onset and is often oliguric (but may be nonoliguric and less obvious). However, there may often be an overlap between “prerenal,” acute renal damage, and postrenal disease, and a mixed picture may be seen since causes are often “multifactorial.”
1. Urinalysis in ATN
a. Urine specific gravity is usually near isosthenuria (1.010).
b. Mild proteinuria is typical (nephritic, usually 1+ to 2+ on a urine dipstick exam) as opposed to nephrotic range proteinuria (which is often 3+ or 4+ on the dipstick).
c. Sediment. Early on, the sediment may be remarkably bland. ATN can often be suspected by the presence of many “dirty brown” granular casts in the urine. Usually, only small numbers of white and red blood cells are seen, except in cases of acute glomerulonephritis. Red blood cell casts are rare. The finding of renal tubular epithelial cells (larger cells with larger nuclei) is diagnostic of renal tubular damage.
2. Several pathogenetic mechanisms are recognized, and multiple mechanisms may be responsible in a given patient. Direct tubular toxicity is likely the mechanism for ATN as a result of aminoglycosides and many chemotherapeutic agents (see Table 31.3). Intratubular obstruction with cellular debris, protein casts, or crystal deposition (uric acid, acyclovir, methotrexate, and sulfa drugs) may play a role. Ischemic injury due to sepsis or shock is probably the most common cause.
Table 31.3 Drugs That Affect the Kidneys of Cancer Patients
a. A careful review of inpatient and outpatient medications is necessary, especially with the increasing use of medications purchased “over the counter” (OTC, such as large doses of vitamins, herbal products, and nonsteroidal anti-inflammatory agents). The patient may fail to mention medications prescribed by other physicians or subspecialists.
b. In today’s increasingly complex medical and computerized environment, the possibility of medication errors and “dropouts” with computerized programs that automatically “drop medications” if not renewed within specific time frames (e.g., 48 hours) require compulsive attention to iatrogenic causes of renal failure or adverse clinical outcomes.
c. In addition to the cumulative and additive effect of drugs causing renal failure in many cases, it is especially important to be aware of “drug–drug,” “drug–OTC medications,” and “drug–herbal medication” interactions. Where the history is incomplete or vague, obtaining a written report of all prescribed medications by the patient’s pharmacy may be surprising in the number and types of medications prescribed, and yield what would otherwise be “occult” etiologies for renal failure.
3. The major histologic findings are death and sloughing of tubular epithelial cells with preservation of tubular basement membranes and evidence of epithelial regeneration (mitotic figures). Proteinaceous casts and inflammatory cells may be present. Glomeruli are generally preserved. The lesion may be spotty with some nephrons appearing nearly normal. Disruption of tubular basement membranes (tubulorrhexis) and disrupted glomeruli suggest cortical necrosis, which carries a poor renal prognosis. Management includes avoidance of fluid imbalance and other supportive measures until function returns. Dialysis may be needed in some cases.
4. Radiocontrast is a particularly important cause of ARF in patients with malignancies because of the frequency with which these patients undergo radiocontrast studies. Predisposing factors include age older than 60 years, diabetes mellitus, volume depletion, other recent radiocontrast studies, high dose of contrast, concomitant nephrotoxic drug therapy, and, possibly, hyperuricemia.
a. Iodinated contrast media are strongly linked to the development of ATN and ARF syndromes, especially in patients with pre-existing renal disease (i.e., elevated serum creatinine). Hyperosmolar contrast agents appear to be more toxic. With the increasing clinical use of isotonic and hypotonic contrast agents, the risk of ARF can be lessened. Intravenous (not oral) hydration using isotonic (normal) saline is superior to 0.45% saline and is the most proven method to prevent or limit consequences of renal tubular damage. The prophylactic use of mannitol, diuretics, or methods other than IV hydration have limited, if any, effect on prevention of contrastinduced renal failure.
b. Nephrogenic systemic fibrosis (NSF) is a relatively recently recognized syndrome that occurs exclusively in patients with kidney disease, especially in patients requiring regular dialysis therapy. Greater than 95% of cases of NSF are associated with intravenous gadolinium used as a “contrast agent” for MRI studies. Different gadolinium contrast agents may be associated with a lesser risk of NSF, which may be irreversible.
Gadolinium is relatively contraindicated in patients with renal insufficiency, especially those on dialysis. We recommend consulting the radiologist to find noncontrast alternative studies or identify the agent with the least risk of renal or other systemic damage. If the study is required, inform the patient of the risks and benefits of obtaining images that require contrast agents.
5. Prevention of ATN is often difficult in complicated patients who may be septic or hypotensive and who may have received or required nephrotoxic drugs and/or participated in studies using radiocontrast materials. The following measures are reasonable:
a. Avoid nephrotoxic agents (or use alternative agents when possible) and monitor drug levels when such drugs are needed. Since some drugs like aminoglycosides are reflective and essential markers of GFR, higher levels may reflect renal damage and diminished excretion. Thus, increased drug levels are reflective of not only the need for dosage adjustment but also worsening renal function.
b. Keep patients optimally hydrated with attention to intravascular volume, frequent monitoring of vital signs including BP, pulse rate, cardiac output, urine volume, and, if needed, continuous monitoring of the electrocardiogram and oxygen saturation. When feasible and safe, monitoring BP and pulse in supine, sitting, and standing positions (to detect early orthostatic changes that are reflective of ECV) should be done. A clinical pearl for effective ECV is the physician standing at the foot of the patient’s bed, noting warm and pink toes with urine flowing.
c. Maintain high urine flow rates in patients at risk of crystal deposition in tubules, with fluids and, when necessary, loop diuretics, and alkalinize the urine for patients with rhabdomyolysis, hyperuricemia, or high-dose methotrexate therapy.
d. Prevention of radiocontrast-induced ATN is best managed by hydrating patients and avoiding serial studies in a short period of time. Most patients can tolerate 1 L of normal saline administered intravenously over 2 to 6 hours before the procedure. Data also support the use of N-acetylcysteine (Mucomyst) 600 mg PO twice daily on the day preceding and the day of the procedure.
Small series suggest benefit from the selective dopamine (D1) receptor agonist fenoldopam (Corlopam) given at a dose of 1 µg/kg/min 1 hour prior to procedure. Animal data suggest a benefit from intravenous mannitol; however, data in humans are not compelling. The use of loop diuretics is not supported by current data. The use of low-ionic contrast has been somewhat disappointing. However, recent data with nonionic, iso-osmolar, dimeric contrast agents are more promising.
C. Tubulointerstitial nephritis occurs acutely after the administration of a growing list of drugs but can occur more insidiously after 6 to 12 months of therapy with nonsteroidal anti-inflammatory drugs (NSAIDs; see Table 31.3). The acute presentation is that of nonoliguric acute renal failure with variable systemic findings of allergic skin rash, fever, or arthralgias. Leukocytosis with eosinophilia may be seen, but pyuria with eosinophiluria is probably more common. Microscopic hematuria is a remarkably frequent finding in acute allergic tubulointerstitial nephritis.
1. Histologically, there is a diffuse inflammatory reaction in the interstitium, sometimes with invasion of tubules by white blood cells. Eosinophils may dominate or may be only minimally present.
2. The renal prognosis is good if the offending agent is discontinued. Anecdotal evidence favors the use of a short course of corticosteroids (40 to 60 mg/d of prednisone) if renal failure is severe or persists. Dialysis is only rarely required.
D. Tumor invasion
1. Primary renal tumors commonly invade renal parenchyma, of course, but renal failure requires extensive bilateral renal involvement and is a rare event. The more common cause of renal failure in patients with primary renal tumors is surgical ablation of renal tissue, the consequence of attempts to extirpate the tumor. Because renal cell carcinomas occur bilaterally in at least 5% of patients, preservation of renal tissue by segmental or heminephrectomy is an option to consider; it is a necessity in the patient with only one kidney if dialysis is to be avoided. Such selective ablative surgery may be impossible if tumor has invaded the renal vein (as it tends to do). Patients with renal vein involvement extending into the inferior vena cava often have degrees of renal vein thrombosis and occasionally consequent renal failure.
2. Solid tumor metastasis to kidneys occurs frequently late in the course of many tumors but is a rare cause of renal failure or death.
3. Lymphoproliferative tumors. Renal involvement is common in acute lymphoblastic leukemia (about half of the cases) and lymphoma. Renal failure is less common but does occur. Urinary findings include mild proteinuria, hematuria, and often tumor cells that, when present, are highly suggestive of renal invasion. Imaging studies show large, poorly functioning kidneys without hydronephrosis. Treatment with local irradiation or chemotherapy is associated with resolution of renal failure and diminution of renal size to or toward normal; both abnormalities may recur with recurrence of the tumor.
E. Acute glomerulonephritis causing renal failure is as rare in patients with underlying malignancies as it is in the general population. Certain lymphoproliferative disorders may result in mixed cryoglobulinemia that can cause rapidly progressive (crescentic) glomerulonephritis. Occasionally, tumor antigen interferon-α can cause membranoproliferative glomerulonephritis, both presumably by immune complex–mediated processes that can result in renal failure (see Section VI).
F. Renal cortical necrosis is a rare cause of ARF secondary to ischemic necrosis of the renal cortex. The lesions are usually caused by significantly diminished renal arterial perfusion secondary to vascular spasm, microvascular injury, or intravascular coagulation. Renal cortical necrosis is usually extensive, although focal and localized forms occur. In most cases, the medulla, juxtamedullary cortex, and a thin rim of subcapsular cortex are spared.
Cases of renal cortical necrosis are usually bilateral. Although the pathogenesis of the disease remains unclear, the presumed initiating factor is intense vasospasm of the small vessels. If this vasospasm is brief and vascular flow is reestablished, ATN results. More prolonged vasospasm can cause necrosis and thrombosis of the distal arterioles and glomeruli, and renal cortical necrosis ensues. In hemolytic–uremic syndrome, an additional mechanism involves endotoxin-mediated endothelial damage that leads to vascular thrombosis.
G. Renal papillary necrosis (RPN) is characterized by coagulative necrosis of the renal medullary pyramids and papillae brought on by several associated conditions and toxins that exhibit synergism toward the development of ischemia. The clinical course of RPN varies, depending on the degree of vascular impairment, the presence of associated causal factors, the overall health of the patient, the presence of bilateral involvement, and, specifically, the number of affected papillae.
1. RPN can lead to secondary infection of desquamated necrotic foci, deposition of calculi, and/or separation and eventual sloughing of papillae, with impending acute urinary tract obstruction. Multiple sloughed papillae can obstruct their respective calyces or can congregate and embolize to more distal sites (e.g., ureteropelvic junction, ureter, ureterovesical junction). Previously undiagnosed congenital anomalies (e.g., partial ureteropelvic junction obstruction) can provide a narrowed area where the sloughed papilla can nest and obstruct.
2. RPN is potentially disastrous and, in the presence of bilateral involvement or an obstructed solitary kidney, may lead to renal failure. The infectious sequelae of renal papillary necrosis are more serious if the patient has multiple medical problems, particularly diabetes mellitus.
V. CHRONIC KIDNEY DISEASE (CKD) IN PATIENTS WITH CANCER. The successful development of advanced medical therapies has led to a dramatic increase in the number of patients living with CKD, those living with successfully treated cancer, and those living with both conditions and other illnesses as well. Many countries will allow the patient with progressive and advanced kidney disease artificial kidney treatments (dialysis) or kidney transplantation. In the United States, there are estimated to be nearly 30 million individuals with or at risk of CKD, with perhaps 400,000 to 500,000 receiving regular dialysis therapy.
A. Classification of CKD. Rather than the clinician asking “what is the creatinine level,” which is a poor marker of GFR as noted above, modern evaluation of the patient with CKD involves categorization from stage 0 through stage 5 according to the National Kidney Foundation guidelines as follows:
Stage 0: GFR ≥ 90 mL/min/1.73 m2. The patient is at increased risk of CKD (e.g., diabetes, hypertension, family history of kidney disease). Management involves reduction of CKD risk.
Stage 1: GFR ≥ 90 mL/min/1.73 m2. The patient has urinary abnormalities (e.g., hematuria, proteinuria). Management involves treatment of comorbid conditions and slowing progression.
Stage 2: GFR 60 to 89 mL/min/1.73 m2. Management involves estimating progression.
Stage 3: GFR 30 to 59 mL/min/1.73 m2. Management involves evaluating and treating complications (e.g., treatment for anemia owing to erythropoietin deficiency, vitamin D deficiency, and secondary hyperparathyroidism).
Stage 4: GFR 15 to 29 mL/min/1.73 m2. Management involves preparation for kidney replacement therapy (e.g., treatment for hyperkalemia, hyponatremia, and significant acid base changes).
Stage 5: GFR ≤ 15 mL/min/1.73 m2; previously termed end-stage renal disease (“ESRD”). Management nearly always requires some form of dialysis or “renal replacement therapies,” including kidney transplantation.
B. CKD in cancer patients. The survival rate at 2 years is significantly lower for cancer patients with kidney disease than those without CKD. This reduced survival has been hypothesized to be related to the cardiovascular complications of CKD, inappropriate drug dose adjustment, or perhaps some combination of these and other factors. With increasingly successful anticancer treatment, patients may develop CKD after recovery from ARF or as a long-term consequence of therapies. CKD has been shown to be associated with increased mortality from liver and urinary tract cancers. Furthermore, there is a graded relationship between severity of renal impairment and cancer mortality. (see Launay-Vacher in Selected Reading). These observations mandate the increasing need for the oncologist and nephrologist to discuss therapies when CKD becomes an issue.
VI. NEPHROTIC SYNDROME. The nephrotic syndrome is an unusual but recognized complication of neoplasms. The syndrome may be caused by glomerular deposits of amyloid, by the deposition of immune complexes, or by less well-defined immunologic mechanisms.
A. Incidence. The incidence of nephrotic syndrome as a consequence of malignancies is unknown. From 6% to 10% of patients with nephrotic syndrome eventually manifest a malignancy, but the duration before clinical onset of the malignancy, the large number of patients with a wide variety of malignancies, and the number of isolated (single) case reports make some associations questionable.
Accordingly, the clinical maxim that “patients older than 50 years of age with nephrotic syndrome should have a diligent search for cancer” probably overstates the case. Thus, we apply the age-appropriate cancer screening tests in nephrotic patients as would be done in the normal population. This includes a careful history and physical examination with attention to the lymphatic system, coupled with a complete blood count, chest radiograph, and stool for occult blood unless symptoms or findings suggest the need for further workup. Colonoscopy should be done in patients over age 50 years or with a family history of colon cancer. Women should undergo mammography and pelvic examination with Papanicolaou smear as part of their routine examination.
Although the 24-hour urine measurement of protein is typically reported, obtaining this is usually difficult. A helpful clinical trick is to measure the urine protein/creatinine ratio on a “spot urine”; a ratio of 3.5 or greater or 4+ protein on a dipstick in a well-hydrated patient is typically seen and diagnostic of nephrotic range proteinuria.
B. Associations of nephrotic syndrome exist with many malignancies, including Hodgkin lymphoma (most common); many other lymphoproliferative disorders (including cutaneous T-cell lymphoma); thymoma; plasma cell myeloma; squamous cell carcinoma; adenocarcinomas of the lung, breast, kidney, thyroid, cervix, prostate, and gastrointestinal tract (including esophagus, stomach, pancreas, and colon); mesothelioma; and multiple melanoma. Membranous nephropathy has been frequently reported in patients undergoing graft versus host disease following bone marrow transplantation.
The nephrotic syndrome may occur simultaneously with the clinical manifestation of malignancy. More often, what appear to be true associations of nephrotic syndrome occur months before or after manifestations of the tumor. Recurrence of previously treated tumor may be heralded by the return of the nephrotic syndrome by weeks or months.
C. Pathology is correlated with the most common tumors (Table 31.4).
Table 31.4 Renal Pathology in the Nephrotic Syndrome Associated with Malignancy
D. Pathogenesis. Because of the similarity between the minimal change lesion seen in lipoid nephrosis and the lesion sometimes seen with Hodgkin lymphoma, a defect in T-lymphocyte function causing the generation of an aberrant T-cell factor (yet to be defined) has been postulated for both of these lesions. Glomerular deposition of immune complexes containing specific tumor antigens, viral antigens, and normal autoantigens has been described in single case reports regarding a number of tumors.
E. Management. Remission of nephrotic syndrome may occur with partial or complete elimination of the tumor, especially in Hodgkin lymphoma. Corticosteroid therapy for tumor-associated nephrotic syndrome is usually ineffective if the tumor cannot be controlled.
VII. RENAL EFFECTS OF ANTICANCER THERAPIES. Chemotherapy can cause nephrotoxicity by a variety of mechanisms. Factors that can potentiate renal dysfunction and contribute to the nephrotoxic potential of antineoplastic drugs include intravascular volume depletion, the concomitant use of other nephrotoxic drugs or radiographic ionic contrast media in patients with or without preexisting renal dysfunction, tumor-related urinary tract obstruction, and intrinsic renal disease that is idiopathic and related to other comorbidities or to the cancer itself.
A. Tumor lysis syndrome (TLS)
1. Mechanism. TLS is an oncologic emergency that is caused by massive tumor cell lysis with the release of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation. Hyperuricemia is a consequence of the catabolism of purine nucleic acids to hypoxanthine and xanthine and then to uric acid via the enzyme xanthine oxidase. Uric acid is poorly soluble in water, particularly in the usually acidic environment in the distal tubules and collecting system of the kidney. Overproduction and overexcretion of uric acid in TLS can lead to crystal precipitation and deposition in the renal tubules, and acute uric acid nephropathy with ARF. Hyperphosphatemia with calcium phosphate deposition in the renal tubules can also cause renal failure.
TLS most often occurs after the initiation of cytotoxic therapy in patients with tumors that have a high proliferative rate, large tumor burden, and high sensitivity to cytotoxic therapy (e.g., particularly with high-grade lymphomas and acute lymphoblastic leukemia).
2. Manifestations. The symptoms associated with TLS largely reflect the associated metabolic abnormalities (hyperkalemia, hyperphosphatemia, and hypocalcemia). They include nausea, vomiting, diarrhea, anorexia, lethargy, hematuria, heart failure, cardiac dysrhythmias, seizures, muscle cramps, tetany, syncope, and possible sudden death.
3. Prevention. The best management of TLS is prevention. The preventive regimen consists of aggressive IV hydration and the administration of hypouricemic agents (allopurinol, rasburicase, or febuxostat). The newer agent, febuxostat, can be given in full dosages in kidney or liver disease.
a. IV hydration is recommended prior to therapy in all patients at intermediate or high risk for TLS. The goal is induction of a high urine output, which will minimize the likelihood of uric acid precipitation in the tubules.
b. Urinary alkalinization. The role of urinary alkalinization (to keep the urine pH as high as 7 since uric acid crystals are more likely to form in an acid urinary environment) with sodium bicarbonate is controversial. Use of sodium bicarbonate is only clearly indicated in patients with metabolic acidosis.
c. Hypouricemic agents
(1) Allopurinol is a hypoxanthine analog that competitively inhibits xanthine oxidase, blocking the metabolism of hypoxanthine and xanthine to uric acid. The usual allopurinol dose in adults is 100 mg/m2 every eight hours (maximum 800 mg/d), is generally initiated 24 to 48 hours before the start of induction chemotherapy, and is continued until there is normalization of serum uric acid and other laboratory evidence of tumor lysis (e.g., elevated serum LDH levels).
(2) Rasburicase (recombinant urate oxidase) is well tolerated, rapidly lowers serum uric acid, and is effective in preventing and treating hyperuricemia in TLS. The rapid reduction in serum uric acid is in contrast to the effect of allopurinol, which decreases uric acid formation and therefore does not acutely reduce the serum uric acid concentration. The recommended rasburicase dose is 0.15 to 0.2 mg/kg once daily for 5 days. However, lower doses (3 to 6 mg) or a shorter duration of therapy (or even as a single dose) may be effective in selected patients, based upon whether the indication is for prevention of TLS or for treatment of established TLS. Rasburicase rather than allopurinol is recommended if pretreatment uric acid levels are ≥8 mg/dL. Rasburicase is contraindicated in pregnant or lactating women and in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency because hydrogen peroxide, a byproduct of uric acid breakdown, can cause severe hemolysis and methemoglobinemia in patients with G6PD deficiency.
(3) Febuxostat (Uloric) is a newer and more potent xanthine oxidase inhibitor, which can be given in renal failure. Febuxostat is 500 times more potent than allopurinol. Flat dosing is given in renal and liver disease. However, in some cases, colchicine may need to be given to prevent acute gout since the drug lowers uric acid quickly.
4. Treatment of electrolyte disturbances is discussed in Chapter 27.
B. Radiation nephritis can occur 6 to 12 months to years after doses to the kidneys exceeding 2,000 cGy as a function of dose and proportion of kidney tissue irradiated. Cases with earlier onset may manifest as severe or malignant hypertension, proteinuria of <2 g/d, and an active urinary sediment with microscopic hematuria and granular casts. Cases occurring later mimic chronic interstitial nephritis with a bland urinary sediment, possible salt wasting, or hyporeninemic hypoaldosteronism. Treatment of either presentation involves controlling the blood pressure when elevated.
C. Drug-induced thrombotic thrombocytopenic purpura/hemolytic–uremic syndrome (TTP–HUS) is discussed in Chapter 34, Section V.C. in “Cytopenias.” The drugs associated with the development of TTP–HUS are
1. Cancer chemotherapy (appears to be related to cumulative dose of the drug): mitomycin C, gemcitabine, cisplatin with or without bleomycin, cyclosporine, tacrolimus, cyclophosphamide (perhaps), and use of radiation and high-dose chemotherapy prior to hematopoietic stem-cell transplantation
2. Immune mediated: quinine, ticlopidine, and, less often, clopidogrel
D. Retinoic acid syndrome. Leukocytes may infiltrate the kidney and cause ARF as part of the retinoic acid syndrome, which is caused by the treatment of acute promyelocytic leukemia with all-trans-retinoic acid (see Chapter 25, Section VII.D). The syndrome responds to corticosteroids.
E. Cisplatin nephrotoxicity
1. Mechanisms include tubular epithelial cell toxicity, vasoconstriction in the renal microvasculature, and proinflammatory effects. Cisplatin nephrotoxicity also appears to be mediated by the organic cation transporter (hOCT2). High peak plasma-free platinum concentrations are associated with an increased risk of ARF. The incidence and severity of renal failure increases with subsequent courses and can eventually become irreversible. Cisplatin may also be associated with a thrombotic microangiopathy with features of TTP–HUS when given with bleomycin.
2. Manifestations. The most important manifestation of cisplatin nephrotoxicity is renal impairment, which can be progressive. Other renal manifestations include urinary magnesium and salt wasting, glucosuria, and aminoaciduria (a Fanconi-like syndrome).
3. Prevention. The standard approach to prevent cisplatin-induced nephrotoxicity is the administration of IV isotonic saline to establish a urine flow of at least 100 mL/h for 2 hours prior to and 2 hours after chemotherapy administration.
a. The optimal hydration regimen to prevent nephrotoxicity associated with cisplatin administration is unclear. Although a number of pharmacologic agents have been evaluated to decrease nephrotoxicity (such as amifostine), none has an established role. Mannitol is frequently used to induce diuresis, although there is no evidence that this is required. The addition of furosemide is generally not required, unless there is evidence of fluid overload.
b. Patients with intraperitoneal tumors may be treated with intraperitoneal cisplatin or carboplatin to achieve high local drug levels and relatively low plasma concentrations. In this setting, IV sodium thiosulfate can be given concurrently to bind covalently with the platinum that enters the systemic circulation. The resulting complex has no systemic or renal toxicity and also has no antitumor effect.
c. Avoid the coadministration of other potentially nephrotoxic agents, such as aminoglycosides, nonsteroidal anti-inflammatory agents, or iodinated contrast media.
d. Generally, avoid using cisplatin among patients with a serum creatinine concentration >1.5 mg/dL or an estimated GFR of <50 mL/min. Possible exceptions are when cisplatin has a proven curative role, such as patients with testicular cancer.
F. Ifosfamide nephrotoxicity
1. Mechanisms. In vitro studies suggest that the metabolite chloracetaldehyde is toxic to the tubular cells, rather than the parent drug or another metabolite acrolein. Another possible mechanism of toxicity may be energy depletion via mitochondrial damage.
2. Manifestations. Although ifosfamide can lead to a mild reduction in GFR, renal injury is primarily manifested by one or more of the following signs of tubular dysfunction:
a. Impairment in proximal tubular function as manifested by renal glucosuria, aminoaciduria, tubular proteinuria (i.e., low-molecular-weight proteins but not albumin), and a marked increase in beta-2-microglobulin excretion
b. Hypophosphatemia induced by decreased proximal tubular phosphate reabsorption
c. Renal potassium wasting
d. Metabolic acidosis with a normal anion gap (hyperchloremic) acidosis due to distal (type 1) or proximal (type 2) renal tubular acidosis
e. Polyuria due to nephrogenic diabetes insipidus (i.e., resistance to antidiuretic hormone) causes a dilute urine and is relatively rare. When polyuria does occur, it is more often an appropriate response to isotonic saline therapy that causes sodium diuresis.
3. Prevention. The cornerstone of prevention of ifosfamide nephrotoxicity is to limit the cumulative dose of the drug. The risk of nephrotoxicity is low at cumulative ifosfamide doses of 60 g/m2 or less, and when toxicity does occur, it is usually mild to moderate. Other modalities, such as mesna and N-acetylcysteine, have been evaluated, but efficacy is unproven.
G. Methotrexate (MTX) nephrotoxicity
1. Mechanisms. MTX is primarily cleared via the kidneys, with about 90% being excreted unchanged in the urine. Thus, any impairment of GFR will result in sustained serum levels of the drug that may induce bone marrow or other toxicities. At low doses, MTX is not nephrotoxic. However, high-dose MTX (HDMTX) can affect the kidneys in two different ways:
a. MTX can precipitate in the tubules and directly induce tubular injury. The risk is increased in the presence of acidic urine with volume depletion and when high plasma MTX concentrations are sustained.
b. MTX also causes a transient decline in GFR after each dose, with complete recovery within six to eight hours. The mechanism responsible for this functional renal impairment involves afferent arteriolar constriction or mesangial cell constriction.
2. Manifestations. MTX-induced ARF is typically nonoliguric and is reversible in almost all cases within one to three weeks. The major risk with MTX-induced renal dysfunction is that MTX clearance is severely compromised, resulting in delayed excretion of the drug, higher-than-expected plasma concentrations, and increased systemic toxicity.
3. Prevention. The likelihood of HDMTX-induced renal dysfunction can be minimized (but not eliminated) by hydration both to maintain a high urine flow and to lower the concentration of MTX in the tubular fluid and by alkalinization of the urine to a pH above 7.0.
H. Bisphosphonate nephrotoxicity
1. Mechanisms
a. Pamidronate has been associated with the development of nephrotic syndrome due to a number of different mechanisms, including collapsing focal segmental glomerulosclerosis. Most cases are reported in patients with multiple myeloma.
b. Zoledronic acid. Significant renal impairment attributable to zoledronic acid is uncommon, and appears to be predominantly associated with higher doses, and with infusion durations <15 minutes. The mechanism of nephrotoxicity appears to be different from that in patients receiving pamidronate.
2. Management and prevention. Serum creatinine should be monitored prior to each dose of pamidronate or zoledronic acid. Otherwise, unexplained azotemia (an increase of ≥0.5 mg/dL in serum creatinine or an absolute level of >1.4 mg/dL among patients with normal baseline values) should prompt temporary discontinuation of the bisphosphonate.
a. Restarting bisphosphonates. One can consider increasing the infusion time of pamidronate to more than 2 hours and of zoledronic acid to 30 to 60 minutes every 4 weeks if renal function returns to within 10% of baseline.
b. Hypocalcemia. Most patients receiving high-potency bisphosphonates do not become hypocalcemic because of compensatory mechanisms. However, in some cases, these compensatory mechanisms may be blocked (e.g., prior parathyroidectomy, low vitamin D levels, hypomagnesemic hypoparathyroidism, renal failure) and result in hypocalcemia.
I. Miscellaneous renal issues regarding anticancer therapy
1. Other potentially nephrotoxic chemotherapeutic agents
a. Carboplatin may cause reversible tubular injury manifested by hypomagnesemia and recurrent salt wasting but rarely causes ARF.
b. Vinca alkaloids can result in hyponatremia by inducing the syndrome of inappropriate antidiuretic hormone (SIADH) secretion.
c. Nitrosoureas may cause interstitial nephritis with progressive renal failure via glomerular sclerosis and tubular fibrosis. Streptozocin causes proteinuria commonly, as well as other tubular syndromes, via proximal tubular damage.
d. Monoclonal antibodies
(1) Bevacizumab may cause proteinuria or the nephrotic syndrome. The mechanism appears to be a renal thrombotic microangiopathy.
(2) Panitumumab and cetuximab may cause hypomagnesemia. The mechanism appears to be tubular injury.
e. Tyrosine kinase inhibitors. Sorafenib and sunitinib may cause proteinuria or the nephrotic syndrome. The mechanism appears to be a renal thrombotic microangiopathy.
2. Drug handling in dialysis patients. Data on management of cytotoxic chemotherapy drugs and combination regimens in patients undergoing dialysis are scant. Recommendations vary among the various authorities and governing agencies. For patients with renal impairment, careful evaluation of each chemotherapeutic agent must be made for each individual patient.
3. Chemotherapy agents that may require dose reduction in patients with renal insufficiency include arsenic trioxide, bleomycin, capecitabine, carboplatin, cisplatin, cladribine, cyclophosphamide, cytarabine (high dose), daunorubicin, epirubicin, eribulin, etoposide, fludarabine, hydroxyurea, ifosfamide, irinotecan, lenalidomide, lomustine, melphalan, methotrexate, mitomycin, pentostatin, pemetrexed, sorafenib, streptozocin, and topotecan.
Suggested Reading
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Giraldez M, Puto K. A single, fixed dose of rasburicase (6 mg maximum) for treatment of tumor lysis syndrome in adults. Eur J Haematol 2010;85:177.
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