InternalMed_Harrison

InternalMed_Harrison. of conservative management, including nasogastric decompression. Percutaneous endoscopic or surgical gastrostomy tube placement is an option for palliation of nausea and vomiting, the so-called “venting gastrostomy.” Treatment with antiemetics, antispasmodics, and analgesics may allow patients to remain outside the hospital. Octreotide may relieve obstructive symptoms through its inhibitory effect on gastrointestinal secretion. Glucocorticoids have anti-inflammatory effects and may help the resolution of bowel obstruction. They also have antiemetic effects.


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InternalMed_Harrison. Urinary obstruction may occur in patients with prostatic or gynecologic malignancies, particularly cervical carcinoma; metastatic disease from other primary sites such as carcinomas of the breast, stomach, lung, colon, and pancreas; or lymphomas. Radiation therapy to pelvic tumors may cause fibrosis and subsequent ureteral obstruction. Bladder outlet obstruction is usually due to prostate and cervical cancers and may lead to bilateral hydronephrosis and renal failure.


InternalMed_Harrison

InternalMed_Harrison. Flank pain is the most common symptom. Persistent urinary tract infection, persistent proteinuria, or hematuria in patients with cancer should raise suspicion of ureteral obstruction. Total anuria and/or anuria alternating with polyuria may occur. A slow, continuous rise in the serum creatinine level necessitates immediate evaluation. Renal ultrasound is the safest and cheapest way to identify hydronephrosis. The function of an obstructed kidney can be evaluated by a nuclear scan. CT scan can reveal the point of obstruction and identify a retro-peritoneal mass or adenopathy.


InternalMed_Harrison

InternalMed_Harrison. Obstruction associated with flank pain, sepsis, or fistula formation is an indication for immediate palliative urinary diversion. Internal ureteral stents can be placed under local anesthesia. Percutaneous nephrostomy offers an alternative approach for drainage. The placement of a nephrostomy is associated with a significant rate of pyelonephritis. In the case of bladder outlet obstruction due to malignancy, a suprapubic cystostomy can be used for urinary drainage. An aggressive intervention with invasive approaches to improve the obstruction should be weighed against the likelihood of antitumor response, and the ability to reverse renal insufficiency should be evaluated.


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InternalMed_Harrison. This common clinical problem can be caused by a primary carcinoma arising in the pancreas, ampulla of Vater, bile duct, or liver or by metastatic disease to the periductal lymph nodes or liver parenchyma. The most common metastatic tumors causing biliary obstruction are gastric, colon, breast, and lung cancers. Jaundice, light-colored stools, dark urine, pruritus, and weight loss due to malabsorption are usual symptoms. Pain and secondary infection are uncommon in malignant biliary obstruction. Ultrasound, CT scan, or percutaneous transhepatic or endoscopic retrograde cholangiography will identify the site and nature of the biliary obstruction.


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InternalMed_Harrison. Palliative intervention is indicated only in patients with disabling pruritus resistant to medical treatment, severe malabsorption, or infection. Stenting under radiographic control, surgical bypass, or radiation therapy with or without chemotherapy may alleviate the obstruction. The choice of therapy should be based on the site of obstruction (proximal vs distal), the type of tumor (sensitive to radiotherapy, chemotherapy, or neither), and the general condition of the patient. In the absence of pruritus, biliary obstruction may be a largely asymptomatic cause of death.


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InternalMed_Harrison. Malignant spinal cord compression (MSCC) is defined as compression of the spinal cord and/or cauda equina by an extradural tumor mass. The minimum radiologic evidence for cord compression is indentation of the theca at the level of clinical features. Spinal cord compression occurs in 5–10% of patients with cancer. Epidural tumor is the first manifestation of malignancy in about 10% of patients. The underlying cancer is usually identified during the initial evaluation; lung cancer is the most common cause of MSCC.


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InternalMed_Harrison. Metastatic tumor involves the vertebral column more often than any other part of the bony skeleton. Lung, breast, and prostate cancer are the most frequent offenders. Multiple myeloma also has a high incidence of spine involvement. Lymphomas, melanoma, renal cell cancer, and genitourinary cancers also cause cord compression. The thoracic spine is the most common site (70%), followed by the lumbosacral spine (20%) and the cervical spine (10%). Involvement of multiple sites is most frequent in patients with breast and prostate carcinoma. Cord injury develops when metastases to the vertebral body or pedicle enlarge and compress the underlying dura. Another cause of cord compression is direct extension of a paravertebral lesion through the intervertebral foramen. These cases usually involve a lymphoma, myeloma, or pediatric neoplasm. Parenchymal spinal cord metastasis due to hematogenous spread is rare. Intramedullary metastases can be seen in lung cancer, breast cancer, renal cancer,


InternalMed_Harrison

InternalMed_Harrison. a lymphoma, myeloma, or pediatric neoplasm. Parenchymal spinal cord metastasis due to hematogenous spread is rare. Intramedullary metastases can be seen in lung cancer, breast cancer, renal cancer, melanoma, and lymphoma and are frequently associated with brain metastases and leptomeningeal disease.


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InternalMed_Harrison. Expanding extradural tumors induce injury through several mechanisms. Obstruction of the epidural venous plexus leads to edema. Local production of inflammatory cytokines enhances blood flow and edema formation. Compression compromises blood flow, leading to ischemia. Production of vascular endothelial growth factor is associated with spinal cord hypoxia and has been implicated as a potential cause of damage after spinal cord injury.


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InternalMed_Harrison. The most common initial symptom in patients with spinal cord compression is localized back pain and tenderness due to involvement of vertebrae by tumor. Pain is usually present for days or months before other neurologic findings appear. It is exacerbated by movement and by coughing or sneezing. It can be differentiated from the pain of disk disease by the fact that it worsens when the patient is supine. Radicular pain is less common than localized back pain and usually develops later. Radicular pain in the cervical or lumbosacral areas may be unilateral or bilateral. Radicular pain from the thoracic roots is often bilateral and is described by patients as a feeling of tight, band-like constriction around the thorax and abdomen. Typical cervical radicular pain radiates down the arm; in the lumbar region, the radiation is down the legs. Lhermitte’s sign, a tingling or electric sensation down the back and upper and lower limbs upon flexing or extending the neck, may be an early sign of


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InternalMed_Harrison. lumbar region, the radiation is down the legs. Lhermitte’s sign, a tingling or electric sensation down the back and upper and lower limbs upon flexing or extending the neck, may be an early sign of cord compression. Loss of bowel or bladder control may be the presenting symptom but usually occurs late in the course. Occasionally patients present with ataxia of gait without motor and sensory involvement due to involvement of the spinocerebellar tract.


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InternalMed_Harrison. On physical examination, pain induced by straight leg raising, neck flexion, or vertebral percussion may help to determine the level of cord compression. Patients develop numbness and paresthesias in the extremities or trunk. Loss of sensibility to pinprick is as common as loss of sensibility to vibration or position. The upper limit of the zone of sensory loss is often one or two vertebrae below the site of compression. Motor findings include weakness, spasticity, and abnormal muscle stretching. An extensor plantar reflex reflects significant compression. Deep tendon reflexes may be brisk. Motor and sensory loss usually precedes sphincter disturbance. Patients with autonomic dysfunction may present with decreased anal tonus, decreased perineal sensibility, and a distended bladder. The absence of the anal wink reflex or the bulbocavernosus reflex confirms cord involvement. In doubtful cases, evaluation of postvoiding urinary residual volume can be helpful. A residual volume of >150 mL


InternalMed_Harrison

InternalMed_Harrison. of the anal wink reflex or the bulbocavernosus reflex confirms cord involvement. In doubtful cases, evaluation of postvoiding urinary residual volume can be helpful. A residual volume of >150 mL suggests bladder dysfunction. Autonomic dysfunction is an unfavorable prognostic factor. Patients with progressive neurologic symptoms should have frequent neurologic examinations and rapid therapeutic intervention. Other illnesses that may mimic cord compression include osteoporotic vertebral collapse, disk disease, pyogenic abscess or vertebral tuberculosis, radiation myelopathy, neoplastic leptomeningitis, benign tumors, epidural hematoma, and spinal lipomatosis.


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InternalMed_Harrison. Cauda equina syndrome is characterized by low back pain; diminished sensation over the buttocks, posterior-superior thighs, and perineal area in a saddle distribution; rectal and bladder dysfunction; sexual impotence; absent bulbocavernous, patellar, and Achilles’ reflexes; and variable amount of lower-extremity weakness. This reflects compression of nerve roots as they form the cauda equina after leaving the spinal cord. The majority of cauda equine tumors are primary tumors of glial or nerve sheath origin; metastases are very rare.


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InternalMed_Harrison. Patients with cancer who develop back pain should be evaluated for spinal cord compression as quickly as possible (Fig. 331-2). Treatment is more often successful in patients who are ambulatory and still have sphincter control at the time treatment is initiated. Patients should have a neurologic examination and plain films of the spine. Those whose physical examination suggests cord compression should receive dexamethasone (6 mg intravenously every 6 h), starting immediately.


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InternalMed_Harrison. Erosion of the pedicles (the “winking owl” sign) is the earliest radiologic finding of vertebral tumor. Other radiographic changes include increased intrapedicular distance, vertebral destruction, lytic or sclerotic lesions, scalloped vertebral bodies, and vertebral body collapse. Vertebral collapse is not a reliable indicator of the presence of tumor; about 20% of cases of vertebral collapse, particularly those in older patients and postmenopausal women, are due not to cancer but 1791 to osteoporosis. Also, a normal appearance on plain films of the spine does not exclude the diagnosis of cancer. The role of bone scans in the detection of cord compression is not clear; this method is sensitive but less specific than spinal radiography.


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InternalMed_Harrison. The full-length image of the cord provided by MRI is the imaging procedure of choice. Multiple epidural metastases are noted in 25% of patients with cord compression, and their presence influences treatment plans. On T1-weighted images, good contrast is noted between the cord, cerebrospinal fluid, and extradural lesions. Owing to its sensitivity in demonstrating the replacement of bone marrow by tumor, MRI can show which parts of a vertebra are involved by tumor. MRI also visualizes intraspinal extradural masses compressing the cord. T2-weighted images are most useful for the demonstration of intramedullary pathology. Gadolinium-enhanced MRI can help to delineate intramedullary disease. MRI is as good as or better than myelography plus postmyelogram CT scan in detecting metastatic epidural disease with cord compression. Myelography should be reserved for patients who have poor MRIs or who cannot undergo MRI promptly. CT scan in conjunction with myelography enhances the detection of


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InternalMed_Harrison. disease with cord compression. Myelography should be reserved for patients who have poor MRIs or who cannot undergo MRI promptly. CT scan in conjunction with myelography enhances the detection of small areas of spinal destruction.


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InternalMed_Harrison. In patients with cord compression and an unknown primary tumor, a simple workup including chest radiography, mammography, measurement of prostate-specific antigen, and abdominal CT usually reveals the underlying malignancy. The treatment of patients with spinal cord compression is aimed at relief of pain and restoration/preservation of neurologic function (Fig. 331-2). Management of MSCC requires a multidisciplinary approach. CHAPTER 331 Symptomatic therapy Back pain Neurologic exam Plain spine x-ray High-dose dexamethasone MRI of spine Bone metastases but no epidural metastases Symptomatic therapy ±radiation therapy Epidural metastases No metastases Surgery followed by radiation therapy or radiation therapy alone Symptomatic therapy Pain crescendo pattern Lhermitte’s sign Pain aggravated with cough, Valsalva, and recumbency Abnormal Normal Normal Suspicious for myelopathy FIGURE 331-2 Management of cancer patients with back pain.


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InternalMed_Harrison. 1792 Radiation therapy plus glucocorticoids is generally the initial treatment of choice for most patients with spinal cord compression. Up to 75% of patients treated when still ambulatory remain ambulatory, but only 10% of patients with paraplegia recover walking capacity. Indications for surgical intervention include unknown etiology, failure of radiation therapy, a radioresistant tumor type (e.g., melanoma or renal cell cancer), pathologic fracture dislocation, and rapidly evolving neurologic symptoms. Laminectomy is done for tissue diagnosis and for the removal of posteriorly localized epidural deposits in the absence of vertebral body disease. Because most cases of epidural spinal cord compression are due to anterior or anterolateral extradural disease, resection of the anterior vertebral body along with the tumor, followed by spinal stabilization, has achieved good results. A randomized trial showed that patients who underwent an operation followed by radiotherapy (within 14


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InternalMed_Harrison. body along with the tumor, followed by spinal stabilization, has achieved good results. A randomized trial showed that patients who underwent an operation followed by radiotherapy (within 14 days) retained the ability to walk significantly longer than those treated with radiotherapy alone. Surgically treated patients also maintained continence and neurologic function significantly longer than patients in the radiation group. The length of survival was not significantly different in the two groups, although there was a trend toward longer survival in the surgery group. The study drew some criticism for the poorer than expected results in the patients who did not go to surgery. The benefit of surgery over radiotherapy decreased in patients over age 65 years. However, patients should be evaluated for surgery if they are expected to survive longer than 3 months. Conventional radiotherapy has a role after surgery. Chemotherapy may have a role in patients with chemosensitive tumors who have


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InternalMed_Harrison. for surgery if they are expected to survive longer than 3 months. Conventional radiotherapy has a role after surgery. Chemotherapy may have a role in patients with chemosensitive tumors who have had prior radiotherapy to the same region and who are not candidates for surgery. Most patients with prostate cancer who develop cord compression have already had hormonal therapy; however, for those who have not, androgen deprivation is combined with surgery and radiotherapy. Patients who previously received radiotherapy for MSCC with an in-field tumor progression can be treated with reirradiation if they are not surgical candidates. Patients with metastatic vertebral tumors may benefit from percutaneous vertebroplasty or kyphoplasty, the injection of acrylic cement into a collapsed vertebra to stabilize the fracture. Pain palliation is common, and local antitumor effects have been noted. Cement leakage may cause symptoms in about 10% of patients. Bisphosphonates may be helpful in prevention


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InternalMed_Harrison. the fracture. Pain palliation is common, and local antitumor effects have been noted. Cement leakage may cause symptoms in about 10% of patients. Bisphosphonates may be helpful in prevention of SCC in patients with bony involvement. The histology of the tumor is an important determinant of both recovery and survival. Rapid onset and progression of signs and symptoms are poor prognostic features.


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InternalMed_Harrison. About 25% of patients with cancer die with intracranial metastases. The cancers that most often metastasize to the brain are lung and breast cancers and melanoma. Brain metastases often occur in the presence of systemic disease, and they frequently cause major symptoms, disability, and early death. The initial presentation of brain metastases from a previously unknown primary cancer is common. Lung cancer is most commonly the primary malignancy. Chest/ abdomen CT scans and brain MRI as the initial diagnostic studies can identify a biopsy site in most patients.


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InternalMed_Harrison. The signs and symptoms of a metastatic brain tumor are similar to those of other intracranial expanding lesions: headache, nausea, vomiting, behavioral changes, seizures, and focal, progressive neurologic changes. Occasionally the onset is abrupt, resembling a stroke, with the sudden appearance of headache, nausea, vomiting, and neurologic deficits. This picture is usually due to hemorrhage into the metastasis. Melanoma, germ cell tumors, and renal cell cancers have a particularly high incidence of intracranial bleeding. The tumor mass and surrounding edema may cause obstruction of the circulation of cerebrospinal fluid, with resulting hydrocephalus. Patients with increased intracranial pressure may have papilledema with visual disturbances and neck stiffness. As the mass enlarges, brain tissue may be displaced through the fixed cranial openings, producing various herniation syndromes.


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InternalMed_Harrison. CT scan and MRI are equally effective in the diagnosis of brain metastases. CT scan with contrast should be used as a screening procedure. The CT scan shows brain metastases as multiple enhancing lesions of various sizes with surrounding areas of low-density edema. If a single lesion or no metastases are visualized by contrast-enhanced CT, MRI of the brain should be performed. Gadolinium-enhanced MRI is more sensitive than CT at revealing meningeal involvement and small lesions, particularly in the brainstem or cerebellum. Intracranial hypertension (“pseudotumor cerebri”) secondary to tretinoin therapy has been reported.


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InternalMed_Harrison. Dexamethasone is the best initial treatment for all symptomatic patients with brain metastases. Patients with multiple lesions should usually receive whole-brain radiation. Patients with a single brain metastasis and with controlled extracranial disease may be treated with surgical excision followed by whole-brain radiation therapy, especially if they are younger than 60 years. Radioresistant tumors should be resected if possible. Stereotactic radiosurgery (SRS) is recommended in patients with a limited number of brain metastases (one to four) who have stable, systemic disease or reasonable systemic treatment options and for patients who have a small number of metastatic lesions in whom whole-brain radiation therapy has failed. With a gamma knife or linear accelerator, multiple small, well-collimated beams of ionizing radiation destroy lesions seen on MRI. Some patients with increased intracranial pressure associated with hydrocephalus may benefit from shunt placement. If neurologic


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InternalMed_Harrison. beams of ionizing radiation destroy lesions seen on MRI. Some patients with increased intracranial pressure associated with hydrocephalus may benefit from shunt placement. If neurologic deterioration is not reversed with medical therapy, ventriculotomy to remove cerebrospinal fluid (CSF) or craniotomy to remove tumors or hematomas may be necessary.


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InternalMed_Harrison. Tumor involving the leptomeninges is a complication of both primary central nervous system (CNS) tumors and tumors that metastasize to the CNS. The incidence is estimated at 3–8% of patients with cancer. Melanoma, breast and lung cancer, lymphoma (including AIDS-associated), and acute leukemia are the most common causes. Synchronous intraparenchymal brain metastases are evident in 11–31% of patients with neoplastic meningitis. Leptomeningeal seeding is frequent in patients undergoing resection of brain metastases or receiving stereotactic radiotherapy for brain metastases. Patients typically present with multifocal neurologic signs and symptoms, including headache, gait abnormality, mental changes, nausea, vomiting, seizures, back or radicular pain, and limb weakness. Signs include cranial nerve palsies, extremity weakness, paresthesia, and decreased deep tendon reflexes.


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InternalMed_Harrison. Diagnosis is made by demonstrating malignant cells in the CSF; however, up to 40% of patients may have false-negative CSF cytology. An elevated CSF protein level is nearly always present (except in HTLV-1–associated adult T cell leukemia). Patients with neurologic signs and symptoms consistent with neoplastic meningitis who have a negative CSF cytology but an elevated CSF protein level should have the spinal tap repeated at least three times for cytologic examination before the diagnosis is rejected. MRI findings suggestive of neoplastic meningitis include leptomeningeal, subependymal, dural, or cranial nerve enhancement; superficial cerebral lesions; intradural nodules; and communicating hydrocephalus. Spinal cord imaging by MRI is a necessary component of the evaluation of nonleukemia neoplastic meningitis because ~20% of patients have cord abnormalities, including intradural enhancing nodules that are diagnostic for leptomeningeal involvement. Cauda equina lesions are common, but


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InternalMed_Harrison. neoplastic meningitis because ~20% of patients have cord abnormalities, including intradural enhancing nodules that are diagnostic for leptomeningeal involvement. Cauda equina lesions are common, but lesions may be seen anywhere in the spinal canal. The value of MRI for the diagnosis of leptomeningeal disease is limited in patients with hematopoietic malignancy. Radiolabeled CSF flow studies are abnormal in up to 70% of patients with neoplastic meningitis; ventricular outlet obstruction, abnormal flow in the spinal canal, or impaired flow over the cerebral convexities may affect distribution of intrathecal chemotherapy, resulting in decreased efficacy or increased toxicity. Radiation therapy may correct CSF flow abnormalities before use of intrathecal chemotherapy. Neoplastic meningitis can also lead to intracranial hypertension and hydrocephalus. Placement of a ventriculoperitoneal shunt may effectively palliate symptoms in these patients.


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InternalMed_Harrison. The development of neoplastic meningitis usually occurs in the setting of uncontrolled cancer outside the CNS; thus, prognosis is poor (median survival 10–12 weeks). However, treatment of the neoplastic meningitis may successfully alleviate symptoms and control the CNS spread. Intrathecal chemotherapy, usually methotrexate, cytarabine, or thiotepa, is delivered by lumbar puncture or by an intraventricular reservoir (Ommaya). An extended-release preparation of cytarabine (Depocyte) has a longer half-life and is more effective than other formulations. Among solid tumors, breast cancer responds best to therapy. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) may be effective in non-small-cell lung cancer patients with EGFR mutations and leptomeningeal involvement. Patients with neoplastic meningitis from either acute leukemia or lymphoma may be cured of their CNS disease if the systemic disease can be eliminated.


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InternalMed_Harrison. Seizures occurring in a patient with cancer can be caused by the tumor itself, by metabolic disturbances, by radiation injury, by cerebral infarctions, by chemotherapy-related encephalopathies, or by CNS infections. Metastatic disease to the CNS is the most common cause of seizures in patients with cancer. However, seizures occur more frequently in primary brain tumors than in metastatic brain lesions. Seizures are a presenting symptom of CNS metastasis in 6–29% of cases. Approximately 10% of patients with CNS metastasis eventually develop seizures. Tumors that affect the frontal, temporal, and parietal lobes are more commonly associated with seizures than are occipital lesions. The presence of frontal lesions correlates with early seizures, and the presence of hemispheric symptoms increases the risk for late seizures. Both early and late seizures are uncommon in patients with posterior fossa and sellar lesions. Seizures are common in patients with CNS metastases from melanoma and


InternalMed_Harrison

InternalMed_Harrison. the risk for late seizures. Both early and late seizures are uncommon in patients with posterior fossa and sellar lesions. Seizures are common in patients with CNS metastases from melanoma and low-grade primary brain tumors. Very rarely, cytotoxic drugs such as etoposide, busulfan, ifosfamide, and chlorambucil cause seizures. Another cause of seizures related to drug therapy is reversible posterior leukoencephalopathy syndrome (RPLS). RPLS is associated rarely with administration of cisplatin, 5-fluorouracil, bleomycin, vinblastine, vincristine, etoposide, paclitaxel, ifosfamide, cyclophosphamide, doxorubicin, cytarabine, methotrexate, oxaliplatin, cyclosporine, tacrolimus, and vascular endothelial growth factor inhibitors including bevacizumab, aflibercept, sunitinib, sorafenib, pazopanib, and axitinib. RPLS occurs in patients undergoing allogeneic bone marrow or solid-organ transplantation. RPLS is characterized by headache, altered consciousness, generalized seizures, visual


InternalMed_Harrison

InternalMed_Harrison. and axitinib. RPLS occurs in patients undergoing allogeneic bone marrow or solid-organ transplantation. RPLS is characterized by headache, altered consciousness, generalized seizures, visual disturbances, hypertension, and posterior cerebral white matter vasogenic edema on CT/MRI. Seizures may begin focally but are typically generalized.


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InternalMed_Harrison. Patients in whom seizures due to CNS metastases have been demonstrated should receive anticonvulsive treatment with phenytoin or levetiracetam. If this is not effective, valproic acid can be added. Prophylactic anticonvulsant therapy is not recommended. In postcraniotomy patients, prophylactic antiepileptic drugs should be withdrawn during the first week after surgery. Most antiseizure medications including phenytoin induce cytochrome P450 (CYP450), which alters the metabolism of many antitumor agents, including irinotecan, taxanes, and etoposide as well as molecular 1793 targeted agents, including imatinib, gefitinib, erlotinib, tipifarnib, sorafenib, sunitinib, temsirolimus, everolimus, and vemurafenib. Levetiracetam and topiramate are anticonvulsant agents not metabolized by the hepatic CYP450 system and do not alter the metabolism of antitumor agents. They have become the preferred drugs. Surgical resection and other antitumor treatments such as radiotherapy and chemotherapy may


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InternalMed_Harrison. CYP450 system and do not alter the metabolism of antitumor agents. They have become the preferred drugs. Surgical resection and other antitumor treatments such as radiotherapy and chemotherapy may improve seizure control.


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InternalMed_Harrison. Hyperleukocytosis and the leukostasis syndrome associated with it is a potentially fatal complication of acute leukemia (particularly myeloid leukemia) that can occur when the peripheral blast cell count is >100,000/mL. The frequency of hyperleukocytosis is 5–13% in acute myeloid leukemia (AML) and 10–30% in acute lymphoid leukemia; however, leukostasis is rare in lymphoid leukemia. At such high blast cell counts, blood viscosity is increased, blood flow is slowed by aggregates of tumor cells, and the primitive myeloid leukemic cells are capable of invading through the endothelium and causing hemorrhage. Brain and lung are most commonly affected. Patients with brain leukostasis may experience stupor, headache, dizziness, tinnitus, visual disturbances, ataxia, confusion, coma, or sudden death. On examination, papilledema, retinal vein distension, retinal hemorrhages, and focal deficit may be present. Administration of 600 cGy of whole-brain irradiation can protect against this


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InternalMed_Harrison. death. On examination, papilledema, retinal vein distension, retinal hemorrhages, and focal deficit may be present. Administration of 600 cGy of whole-brain irradiation can protect against this complication and can be followed by rapid institution of antileukemic therapy. Hydroxyurea, 3–5 g, can rapidly reduce a high blast cell count while the accurate diagnostic workup is in progress. Pulmonary leukostasis may present as respiratory distress and hypoxemia, and progress to respiratory failure. Chest radiographs may be normal but usually show interstitial or alveolar infiltrates. Hyperleukocytosis rarely may cause acute leg ischemia, renal vein thrombosis, myocardial ischemia, bowel infraction, and priapism. Arterial blood gas results should be interpreted cautiously. Rapid consumption of plasma oxygen by the markedly increased number of white blood cells can cause spuriously low arterial oxygen tension. Pulse oximetry is the most accurate way of assessing oxygenation in patients with


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InternalMed_Harrison. plasma oxygen by the markedly increased number of white blood cells can cause spuriously low arterial oxygen tension. Pulse oximetry is the most accurate way of assessing oxygenation in patients with hyperleukocytosis. Leukapheresis may be helpful in decreasing circulating blast counts. Treatment of the leukemia can result in pulmonary hemorrhage from lysis of blasts in the lung, called leukemic cell lysis pneumopathy. Intravascular volume depletion and unnecessary blood transfusions may increase blood viscosity and worsen the leukostasis syndrome. Leukostasis is very rarely a feature of the high white cell counts associated with chronic lymphoid or chronic myeloid leukemia.


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InternalMed_Harrison. When acute promyelocytic leukemia is treated with differentiating agents like tretinoin and arsenic trioxide, cerebral or pulmonary leukostasis may occur as tumor cells differentiate into mature neutrophils. This complication can be largely avoided by using cytotoxic chemotherapy or arsenic together with the differentiating agents.


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InternalMed_Harrison. Hemoptysis may be caused by nonmalignant conditions, but lung cancer accounts for a large proportion of cases. Up to 20% of patients with lung cancer have hemoptysis some time in their course. Endobronchial metastases from carcinoid tumors, breast cancer, colon cancer, kidney cancer, and melanoma may also cause hemoptysis. The volume of bleeding is often difficult to gauge. Massive hemoptysis is defined as >200–600 mL of blood produced in 24 h. However, any hemoptysis should be considered massive if it threatens life. When respiratory difficulty occurs, hemoptysis should be treated emergently. The first priorities are to maintain the airway, optimize oxygenation, and stabilize the hemodynamic status. If the bleeding side is known, the patient should be placed in a lateral decubitus position, with the bleeding side down to prevent aspiration into the unaffected lung, and given supplemental oxygen. If large-volume bleeding continues or the airway is compromised, the patient should be


InternalMed_Harrison

InternalMed_Harrison. with the bleeding side down to prevent aspiration into the unaffected lung, and given supplemental oxygen. If large-volume bleeding continues or the airway is compromised, the patient should be intubated and undergo emergency bronchoscopy. If the site of bleeding is detected, either the patient undergoes a definitive surgical procedure or the lesion is treated with a neodymium:yttrium-aluminum-garnet (Nd:YAG) laser, argon plasma coagulation, or electrocautery. In stable 1794 patients, multidetector CT angiography delineates bronchial and non-bronchial systemic arteries and identifies the source of bleeding and underlying pathology with high sensitivity. Massive hemoptysis usually originates from the high-pressure bronchial circulation. Bronchial artery embolization is considered a first-line definite procedure for managing hemoptysis. Bronchial artery embolization may control brisk bleeding in 75–90% of patients, permitting the definitive surgical procedure to be done more safely.


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InternalMed_Harrison. definite procedure for managing hemoptysis. Bronchial artery embolization may control brisk bleeding in 75–90% of patients, permitting the definitive surgical procedure to be done more safely. Embolization without definitive surgery is associated with rebleeding in 20–50% of patients. Recurrent hemoptysis usually responds to a second embolization procedure. A postembolization syndrome characterized by pleuritic pain, fever, dysphagia, and leukocytosis may occur; it lasts 5–7 days and resolves with symptomatic treatment. Bronchial or esophageal wall necrosis, myocardial infarction, and spinal cord infarction are rare complications. Surgery, as a salvage strategy, is indicated after failure of embolization and is associated with better survival when performed in a nonurgent setting. Pulmonary hemorrhage with or without hemoptysis in hematologic malignancies is often associated with fungal infections, particularly Aspergillus sp. After granulocytopenia resolves, the lung infiltrates in


InternalMed_Harrison

InternalMed_Harrison. hemorrhage with or without hemoptysis in hematologic malignancies is often associated with fungal infections, particularly Aspergillus sp. After granulocytopenia resolves, the lung infiltrates in aspergillosis may cavitate and cause massive hemoptysis. Thrombocytopenia and coagulation defects should be corrected, if possible. Surgical evaluation is recommended in patients with aspergillosis-related cavitary lesions. Bevacizumab, an antibody to vascular endothelial growth factor (VEGF) that inhibits angiogenesis, has been associated with life-threatening hemoptysis in patients with non-small-cell lung cancer, particularly of squamous cell histology. Non-small-cell lung cancer patients with cavitary lesions or previous hemoptysis (≥2.5 mL) within the past 3 months have higher risk for pulmonary hemorrhage.


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InternalMed_Harrison. Airway obstruction refers to a blockage at the level of the mainstem bronchi or above. It may result either from intraluminal tumor growth or from extrinsic compression of the airway. The most common cause of malignant upper airway obstruction is invasion from an adjacent primary tumor, most commonly lung cancer, followed by esophageal, thyroid, and mediastinal malignancies including lymphomas. Extrathoracic primary tumors such as renal, colon, or breast cancer can cause airway obstruction through endobronchial and/or mediastinal lymph node metastases. Patients may present with dyspnea, hemoptysis, stridor, wheezing, intractable cough, postobstructive pneumonia, or hoarseness. Chest radiographs usually demonstrate obstructing lesions. CT scans reveal the extent of tumor. Cool, humidified oxygen, glucocorticoids, and ventilation with a mixture of helium and oxygen (Heliox) may provide temporary relief. If the obstruction is proximal to the larynx, a tracheostomy may be lifesaving. For


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InternalMed_Harrison. oxygen, glucocorticoids, and ventilation with a mixture of helium and oxygen (Heliox) may provide temporary relief. If the obstruction is proximal to the larynx, a tracheostomy may be lifesaving. For more distal obstructions, particularly intrinsic lesions incompletely obstructing the airway, bronchoscopy with mechanical debulking and dilatation or ablational treatments including laser treatment, photodynamic therapy, argon plasma coagulation, electrocautery, or stenting can produce immediate relief in most patients (Fig. 331-3). However, radiation therapy (either external-beam irradiation or brachytherapy) given together with glucocorticoids may also open the airway. Symptomatic extrinsic compression may be palliated by stenting. Patients with primary airway tumors such as squamous cell carcinoma, carcinoid tumor, adenocystic carcinoma, or non-small-cell lung cancer, if resectable, should have surgery.


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InternalMed_Harrison. Hypercalcemia is the most common paraneoplastic syndrome. Its pathogenesis and management are discussed fully in Chaps. 121 and 424. Hyponatremia is a common electrolyte abnormality in cancer patients, and SIADH is the most common cause among patients with cancer. SIADH is discussed fully in Chaps. 121 and 401e. FIGURE 331-3 Airway obstruction. A. Computed tomography scan of a 62-year-old man with tracheal obstruction caused by renal carci-noma showing paratracheal mass with tracheal invasion/obstruction (arrow). B. Chest x-ray of same patient after stent (arrows) placement.


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InternalMed_Harrison. Lactic acidosis is a rare and potentially fatal metabolic complication of cancer. Lactic acidosis associated with sepsis and circulatory failure is a common preterminal event in many malignancies. Lactic acidosis in the absence of hypoxemia may occur in patients with leukemia, lymphoma, or solid tumors. In some cases, hypoglycemia also is present. Extensive involvement of the liver by tumor is often present. In most cases, decreased metabolism and increased production by the tumor both contribute to lactate accumulation. Tumor cell overexpression of certain glycolytic enzymes and mitochondrial dysfunction can contribute to its increased lactate production. HIV-infected patients have an increased risk of aggressive lymphoma; lactic acidosis that occurs in such patients may be related either to the rapid growth of the tumor or from toxicity of nucleoside reverse transcriptase inhibitors. Symptoms of lactic acidosis include tachypnea, tachycardia, change of mental status, and


InternalMed_Harrison

InternalMed_Harrison. either to the rapid growth of the tumor or from toxicity of nucleoside reverse transcriptase inhibitors. Symptoms of lactic acidosis include tachypnea, tachycardia, change of mental status, and hepatomegaly. The serum level of lactic acid may reach 10–20 mmol/L (90–180 mg/dL). Treatment is aimed at the underlying disease. The danger from lactic acidosis is from the acidosis, not the lactate. Sodium bicarbonate should be added if acidosis is very severe or if hydrogen ion production is very rapid and uncontrolled. Other treatment options include renal replacement therapy, such as hemodialysis, and thiamine replacement. The prognosis is poor regardless of the treatment offered.


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InternalMed_Harrison. Persistent hypoglycemia is occasionally associated with tumors other than pancreatic islet cell tumors. Usually these tumors are large; tumors of mesenchymal origin, hepatomas, or adrenocortical tumors may cause hypoglycemia. Mesenchymal tumors are usually located in the retroperitoneum or thorax. Obtundation, confusion, and behavioral aberrations occur in the postabsorptive period and may precede the diagnosis of the tumor. These tumors often secrete incompletely processed insulin-like growth factor II (IGF-II), a hormone capable of activating insulin receptors and causing hypoglycemia. Tumors secreting incompletely processed big IGF-II are characterized by an increased IGF-II to IGF-I ratio, suppressed insulin and C-peptide level, and inappropriately low growth hormone and β-hydroxybutyrate concentrations. Rarely, hypoglycemia is due to insulin secretion by a non-islet cell carcinoma. The development of hepatic dysfunction from liver metastases and increased glucose consumption by


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InternalMed_Harrison. concentrations. Rarely, hypoglycemia is due to insulin secretion by a non-islet cell carcinoma. The development of hepatic dysfunction from liver metastases and increased glucose consumption by the tumor can contribute to hypoglycemia. If the tumor cannot be resected, hypoglycemia symptoms may be relieved by the administration of glucose, glucocorticoids, or glucagon.


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InternalMed_Harrison. Hypoglycemia can be artifactual; hyperleukocytosis from leukemia, myeloproliferative diseases, leukemoid reactions, or colony-stimulating factor treatment can increase glucose consumption in the test tube after blood is drawn, leading to pseudohypoglycemia.


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InternalMed_Harrison. In patients with cancer, adrenal insufficiency may go unrecognized because the symptoms, such as nausea, vomiting, anorexia, and orthostatic hypotension, are nonspecific and may be mistakenly attributed to progressive cancer or to therapy. Primary adrenal insufficiency may develop owing to replacement of both glands by metastases (lung, breast, colon, or kidney cancer; lymphoma), to removal of both glands, or to hemorrhagic necrosis in association with sepsis or anticoagulation. Impaired adrenal steroid synthesis occurs in patients being treated for cancer with mitotane, ketoconazole, or aminoglutethimide or undergoing rapid reduction in glucocorticoid therapy. Rarely, metastatic replacement causes primary adrenal insufficiency as the first manifestation of an occult malignancy. Metastasis to the pituitary or hypothalamus is found at autopsy in up to 5% of patients with cancer, but associated secondary adrenal insufficiency is rare. On the other hand, ipilimumab, an anti-CTLA-4


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InternalMed_Harrison. to the pituitary or hypothalamus is found at autopsy in up to 5% of patients with cancer, but associated secondary adrenal insufficiency is rare. On the other hand, ipilimumab, an anti-CTLA-4 antibody used for treatment of malignant melanoma, may cause autoimmunity including autoimmune-like enterocolitis, hypophysitis, and hepatitis. Autoimmune hypophysitis may present with headache, visual field defects, and pituitary hormone deficiencies manifesting as hypopituitarism, adrenal insufficiency (including adrenal crisis), or hypothyroidism. Anti-CTLA-4-associated hypophysitis symptoms occur at an average of 6–12 weeks after initiation of therapy. The treatment of severe autoimmune toxicity is glucocorticoids. Almost all patients with hypophysitis respond to withdrawal of ipilimumab and glucocorticoid therapy in several days. However, pituitary dysfunction may resolve or may be permanent, requiring longterm therapy and thyroid and testosterone replacement. Peripheral Addison’s disease


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InternalMed_Harrison. therapy in several days. However, pituitary dysfunction may resolve or may be permanent, requiring longterm therapy and thyroid and testosterone replacement. Peripheral Addison’s disease can also be observed with anti-CTLA-4 antibodies. Megestrol acetate, used to manage cancer and HIV-related cachexia, may suppress plasma levels of cortisol and adrenocorticotropic hormone (ACTH). Patients taking megestrol may develop adrenal insufficiency, and even those whose adrenal dysfunction is not symptomatic may have inadequate adrenal reserve if they become seriously ill. Paradoxically, some patients may develop Cushing’s syndrome and/or hyperglycemia because of the glucocorticoid-like activity of megestrol acetate. Cranial irradiation for childhood brain tumors may affect the hypothalamus-pituitary-adrenal axis, resulting in secondary adrenal insufficiency.


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InternalMed_Harrison. Acute adrenal insufficiency is potentially lethal. Treatment of suspected adrenal crisis is initiated after the sampling of serum cortisol and ACTH levels (Chap. 406). Tumor lysis syndrome (TLS) is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia and is caused by the destruction of a large number of rapidly proliferating neoplastic cells. Acidosis may also develop. Acute renal failure occurs frequently.


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InternalMed_Harrison. TLS is most often associated with the treatment of Burkitt’s lym-1795 phoma, acute lymphoblastic leukemia, and other rapidly proliferating lymphomas, but it also may be seen with chronic leukemias and, rarely, with solid tumors. This syndrome has been seen in patients with chronic lymphocytic leukemia after treatment with nucleosides like fludarabine. TLS has been observed with administration of glucocorticoids, hormonal agents such as letrozole and tamoxifen, and monoclonal antibodies such as rituximab and gemtuzumab. TLS usually occurs during or shortly (1–5 days) after chemotherapy. Rarely, spontaneous necrosis of malignancies causes TLS.


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InternalMed_Harrison. Hyperuricemia may be present at the time of chemotherapy. Effective treatment kills malignant cells and leads to increased serum uric acid levels from the turnover of nucleic acids. Owing to the acidic local environment, uric acid can precipitate in the tubules, medulla, and collecting ducts of the kidney, leading to renal failure. Lactic acidosis and dehydration may contribute to the precipitation of uric acid in the renal tubules. The finding of uric acid crystals in the urine is strong evidence for uric acid nephropathy. The ratio of urinary uric acid to urinary creatinine is >1 in patients with acute hyperuricemic nephropathy and <1 in patients with renal failure due to other causes.


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InternalMed_Harrison. Hyperphosphatemia, which can be caused by the release of intracellular phosphate pools by tumor lysis, produces a reciprocal depression in serum calcium, which causes severe neuromuscular irritability and tetany. Deposition of calcium phosphate in the kidney and hyperphosphatemia may cause renal failure. Potassium is the principal intracellular cation, and massive destruction of malignant cells may lead to hyperkalemia. Hyperkalemia in patients with renal failure may rapidly become life-threatening by causing ventricular arrhythmias and sudden death.


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InternalMed_Harrison. The likelihood that TLS will occur in patients with Burkitt’s lymphoma is related to the tumor burden and renal function. Hyperuricemia and high serum levels of lactate dehydrogenase (LDH >1500 U/L), both of which correlate with total tumor burden, also correlate with the risk of TLS. In patients at risk for TLS, pretreatment evaluations should include a complete blood count, serum chemistry evaluation, and urine analysis. High leukocyte and platelet counts may artificially elevate potassium levels (“pseudohyperkalemia”) due to lysis of these cells after the blood is drawn. In these cases, plasma potassium instead of serum potassium should be followed. In pseudohyperkalemia, no electrocardiographic abnormalities are present. In patients with abnormal baseline renal function, the kidneys and retroperitoneal area should be evaluated by sonography and/or CT to rule out obstructive uropathy. Urine output should be watched closely.


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InternalMed_Harrison. Recognition of risk and prevention are the most important steps in the management of this syndrome (Fig. 331-4). The standard preventive approach consists of allopurinol, urinary alkalinization, and aggressive hydration. Urinary alkalization with sodium bicarbonate is controversial. It increases uric acid solubility, but decreases calcium phosphate solubility. If it is used, it should be discontinued when hyperphosphatemia develops. Intravenous allopurinol may be given in patients who cannot tolerate oral therapy. In some cases, uric acid levels cannot be lowered sufficiently with the standard preventive approach. Rasburicase (recombinant urate oxidase) can be effective in these instances, particularly when renal failure is present. Urate oxidase is missing from primates and catalyzes the conversion of poorly soluble uric acid to readily soluble allantoin. Rasburicase acts rapidly, decreasing uric acid levels within hours; however, it may cause hypersensitivity reactions such as


InternalMed_Harrison

InternalMed_Harrison. the conversion of poorly soluble uric acid to readily soluble allantoin. Rasburicase acts rapidly, decreasing uric acid levels within hours; however, it may cause hypersensitivity reactions such as bronchospasm, hypoxemia, and hypotension. Rasburicase should also be administered to high-risk patients for TLS prophylaxis. Rasburicase is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency who are unable to break down hydrogen peroxide, an end product of the urate oxidase reaction. Rasburicase is known to cause ex vivo enzymatic degradation of uric acid in test tube at room temperature. This leads to spuriously low uric acid levels monocytes/macrophages and T and B lymphocytes.


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InternalMed_Harrison. Severe reactions from rituximab have occurred with Maintain hydration by administration of normal or 1/2 normal saline at 3000 mL/m2 per day high numbers (>50 × 109 lymphocytes) of circulating –/+ Keep urine pH at 7.0 or greater by administration of sodium bicarbonate* cells bearing the target antigen (CD20) and have been Administer allopurinol at 300 mg/m2 per day associated with a rapid fall in circulating tumor cells, mild electrolyte evidence of TLS, and very rarely, death. In addition, increased liver enzymes, D-dimer, and LDH and prolongation of the prothrombin time may occur. Diphenhydramine, hydrocortisone, and acetaminophen can often prevent or suppress the infusion-related symptoms. If they occur, the infusion is stopped and restarted at half the initial infusion rate after the symptoms have abated. Severe CRS may require intensive support for acute respiratory distress syndrome (ARDS) and resistant hypotension.


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InternalMed_Harrison. Serum uric acid >8 mg/dL Serum creatinine >1.6 mg/dL If, after 24–48 h Serum uric acid >8 mg/dL Serum creatinine >1.6 mg/dL Correct treatable renal failure (obstruction) Start rasburicase 0.2 mg/kg daily Serum uric acid ˜8.0 mg/dL Serum creatinine ˜1.6 mg/dL Urine pH °7.0 Delay chemotherapy if feasible or start hemodialysis Start chemotherapy ± chemotherapy Monitor serum chemistry every 6–12 h Discontinue bicarbonate administration* If serum potassium >6 meq/L Serum uric acid >10 mg/dL Serum creatinine >10 mg/dL Serum phosphate >10 mg/dL or increasing Symptomatic hypocalcemia present


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InternalMed_Harrison. Hemolytic-uremic syndrome (HUS) and, less commonly, thrombotic thrombocytopenic purpura (TTP) (Chap. 341) may rarely occur after treatment with antineoplastic drugs, including mitomycin, gemcitabine, cisplatin, and bleomycin, and with VEGF inhibitors. It occurs most often in patients with gastric, lung, colorectal, pancreatic, and breast carcinoma. In one series, 35% of patients were without evident cancer at the time this syndrome appeared. Secondary HUS/TTP has also been reported as a rare but sometimes fatal complication of bone marrow transplantation. HUS usually has its onset 4–8 weeks after the last dose of chemotherapy, but it is not rare to detect it several months later. HUS is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. Dyspnea, weakness, fatigue, oliguria, and purpura are also common initial symptoms and findings. Systemic hypertension and pulmonary


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InternalMed_Harrison. FIGURE 331-4 Management of patients at high risk for the tumor lysis syndrome. edema frequently occur. Severe hypertension, pul *See text. monary edema, and rapid worsening of hemolysis and renal function may occur after a blood or blood product transfusion. Cardiac findings include during laboratory monitoring of the patient with TLS. Samples atrial arrhythmias, pericardial friction rub, and pericardial effusion. must be cooled immediately to deactivate the urate oxidase. Despite Raynaud’s phenomenon is part of the syndrome in patients treated aggressive prophylaxis, TLS and/or oliguric or anuric renal failure with bleomycin. may occur. Care should be taken to prevent worsening of symptom-Laboratory findings include severe to moderate anemia associatic hypocalcemia by induction of alkalosis during bicarbonate infu-ated with red blood cell fragmentation and numerous schistocytes sion. Administration of sodium bicarbonate may also lead to urinary on peripheral smear. Reticulocytosis,


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InternalMed_Harrison. during bicarbonate infu-ated with red blood cell fragmentation and numerous schistocytes sion. Administration of sodium bicarbonate may also lead to urinary on peripheral smear. Reticulocytosis, decreased plasma haptoglobin, precipitation of calcium phosphate, which is less soluble at alkaline and an LDH level document hemolysis. The serum bilirubin level is pH. Dialysis is often necessary and should be considered early in the usually normal or slightly elevated. The Coombs’ test is negative. The course. Hemodialysis is preferred. Hemofiltration offers a gradual, white cell count is usually normal, and thrombocytopenia (<100,000/ continuous method of removing cellular by-products and fluid. The μL) is almost always present. Most patients have a normal coagulation prognosis is excellent, and renal function recovers after the uric acid profile, although some have mild elevations in thrombin time and in level is lowered to ≤10 mg/dL. levels of fibrin degradation products. The serum


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InternalMed_Harrison. and renal function recovers after the uric acid profile, although some have mild elevations in thrombin time and in level is lowered to ≤10 mg/dL. levels of fibrin degradation products. The serum creatinine level is elevated at presentation and shows a pattern of subacute worsening within weeks of the initial azotemia. The urinalysis reveals hematuria,


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InternalMed_Harrison. HUMAN ANTIBODY INFUSION REACTIONS proteinuria, and granular or hyaline casts; and circulating immune The initial infusion of human or humanized antibodies (e.g., ritux-complexes may be present. imab, gemtuzumab, trastuzumab, alemtuzumab, panitumumab, bren-The basic pathologic lesion appears to be deposition of fibrin in tuximab vedotin) is associated with fever, chills, nausea, asthenia, the walls of capillaries and arterioles, and these deposits are similar to and headache in up to half of treated patients. Bronchospasm and those seen in HUS due to other causes. These microvascular abnorhypotension occur in 1% of patients. Severe manifestations including malities involve mainly the kidneys and rarely occur in other organs. pulmonary infiltrates, acute respiratory distress syndrome, and cardio-The pathogenesis of cancer treatment–related HUS is not completely genic shock occur rarely. Laboratory manifestations include elevated understood, but probably the most important factor is


InternalMed_Harrison

InternalMed_Harrison. cardio-The pathogenesis of cancer treatment–related HUS is not completely genic shock occur rarely. Laboratory manifestations include elevated understood, but probably the most important factor is endothelial hepatic aminotransferase levels, thrombocytopenia, and prolongation damage. Primary forms of HUS/TTP are related to a decrease in proof prothrombin time. The pathogenesis is thought to be activation cessing of von Willebrand factor by a protease called ADAMTS13. of immune effector processes (cells and complement) and release of The case fatality rate is high; most patients die within a few months. inflammatory cytokines, such as tumor necrosis factor α, interferon There is no consensus on the optimal treatment for chemotherapy-gamma, interleukin 6, and interleukin 10 (cytokine release syndrome induced HUS. Treatment modalities for HUS/TTP including immu[CRS]). Although its origins are not completely understood, CRS is nocomplex removal (plasmapheresis, immunoadsorption, or


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InternalMed_Harrison. release syndrome induced HUS. Treatment modalities for HUS/TTP including immu[CRS]). Although its origins are not completely understood, CRS is nocomplex removal (plasmapheresis, immunoadsorption, or exchange believed to be due to activation of a variety of cell types including transfusion), antiplatelet/anticoagulant therapies, immunosuppressive therapies, and plasma exchange have varying degrees of success. The outcome with plasma exchange is generally poor, as in many other cases of secondary TTP. Rituximab is successfully used in patients with chemotherapy-induced HUS as well as in ADAMTS13deficient TTP.


InternalMed_Harrison

InternalMed_Harrison. These remain the most common serious complications of cancer therapy. They are covered in detail in Chap. 104.


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InternalMed_Harrison. Patients with cancer may present with dyspnea associated with diffuse interstitial infiltrates on chest radiographs. Such infiltrates may be due to progression of the underlying malignancy, treatment-related toxicities, infection, and/or unrelated diseases. The cause may be multifactorial; however, most commonly they occur as a consequence of treatment. Infiltration of the lung by malignancy has been described in patients with leukemia, lymphoma, and breast and other solid cancers. Pulmonary lymphatics may be involved diffusely by neoplasm (pulmonary lymphangitic carcinomatosis), resulting in a diffuse increase in interstitial markings on chest radiographs. The patient is often mildly dyspneic at the onset, but pulmonary failure develops over a period of weeks. In some patients, dyspnea precedes changes on the chest radiographs and is accompanied by a nonproductive cough. This syndrome is characteristic of solid tumors. In patients with leukemia, diffuse microscopic neoplastic


InternalMed_Harrison

InternalMed_Harrison. precedes changes on the chest radiographs and is accompanied by a nonproductive cough. This syndrome is characteristic of solid tumors. In patients with leukemia, diffuse microscopic neoplastic peribronchial and peribronchiolar infiltration is frequent but may be asymptomatic. However, some patients present with diffuse interstitial infiltrates, an alveolar capillary block syndrome, and respiratory distress. In these situations, glucocorticoids can provide symptomatic relief, but specific chemotherapy should always be started promptly.


InternalMed_Harrison

InternalMed_Harrison. Several cytotoxic agents, such as bleomycin, methotrexate, busulfan, nitrosoureas, gemcitabine, mitomycin, vinorelbine, docetaxel, paclitaxel, fludarabine, pentostatin, and ifosfamide may cause pulmonary damage. The most frequent presentations are interstitial pneumonitis, alveolitis, and pulmonary fibrosis. Some cytotoxic agents, including methotrexate and procarbazine, may cause an acute hypersensitivity reaction. Cytosine arabinoside has been associated with noncardiogenic pulmonary edema. Administration of multiple cytotoxic drugs, as well as radiotherapy and preexisting lung disease, may potentiate the pulmonary toxicity. Supplemental oxygen may potentiate the effects of drugs and radiation injury. Patients should always be managed with the lowest FIO2 that is sufficient to maintain hemoglobin saturation.


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InternalMed_Harrison. The onset of symptoms may be insidious, with symptoms including dyspnea, nonproductive cough, and tachycardia. Patients may have bibasilar crepitant rales, end-inspiratory crackles, fever, and cyanosis. The chest radiograph generally shows an interstitial and sometimes an intraalveolar pattern that is strongest at the lung bases and may be symmetric. A small effusion may occur. Hypoxemia with decreased carbon monoxide diffusing capacity is always present. Glucocorticoids may be helpful in patients in whom pulmonary toxicity is related to radiation therapy or to chemotherapy. Treatment is otherwise supportive.


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InternalMed_Harrison. Molecular targeted agents, imatinib, erlotinib, and gefitinib are potent inhibitors of tyrosine kinases. These drugs may cause interstitial lung disease (ILD). In the case of gefitinib, preexisting fibrosis, poor performance status, and prior thoracic irradiation are independent risk factors; this complication has a high fatality rate. In Japan, incidence of interstitial lung disease associated with gefitinib was about 4.5% compared to 0.5% in the United States. Temsirolimus and everolimus, both esters a derivative of rapamycin, are agents that block the effects of mammalian target of rapamycin (mTOR), an enzyme that has an important role in regulating the synthesis of proteins that control cell division. It may cause ground-glass opacities in the lung with or without diffuse interstitial disease and lung parenchymal consolidation. Patients may be asymptomatic with only radiologic findings or may be symptomatic. Symptoms include cough, dyspnea, and/or hypoxemia, and sometimes patients


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InternalMed_Harrison. disease and lung parenchymal consolidation. Patients may be asymptomatic with only radiologic findings or may be symptomatic. Symptoms include cough, dyspnea, and/or hypoxemia, and sometimes patients present with systemic symptoms such as fever and fatigue. The incidence of everolimus-induced interstitial lung disease also appears to be higher in Japanese patients. 1797 Treatment includes dose reduction or withdrawal and, in some cases, the addition of glucocorticoids.


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InternalMed_Harrison. Radiation pneumonitis and/or fibrosis is a relatively frequent side effect of thoracic radiation therapy. It may be acute or chronic. Radiation-induced lung toxicity is a function of the irradiated lung volume, dose per fraction, and radiation dose. The larger the irradiated lung field, the higher is the risk for radiation pneumonitis. The use of concurrent chemoradiation, particularly regimens including paclitaxel, increases pulmonary toxicity. Radiation pneumonitis usually develops 2–6 months after completion of radiotherapy. The clinical syndrome, which varies in severity, consists of dyspnea, cough with scanty sputum, low-grade fever, and an initial hazy infiltrate on chest radiographs. The infiltrate and tissue damage usually are confined to the radiation field. The patients subsequently may develop a patchy alveolar infiltrate and air bronchograms, which may progress to acute respiratory failure that is sometimes fatal. A lung biopsy may be necessary to make the diagnosis.


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InternalMed_Harrison. may develop a patchy alveolar infiltrate and air bronchograms, which may progress to acute respiratory failure that is sometimes fatal. A lung biopsy may be necessary to make the diagnosis. Asymptomatic infiltrates found incidentally after radiation therapy need not be treated. However, prednisone should be administered to patients with fever or other symptoms. The dosage should be tapered slowly after the resolution of radiation pneumonitis, because abrupt withdrawal of glucocorticoids may cause an exacerbation of pneumonia. Delayed radiation fibrosis may occur years after radiation therapy and is signaled by dyspnea on exertion. Often it is mild, but it can progress to chronic respiratory failure. Therapy is supportive.


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InternalMed_Harrison. Classical radiation pneumonitis that leads to pulmonary fibrosis is due to radiation-induced production of local cytokines such as platelet-derived growth factor β, tumor necrosis factor, interleukins, and transforming growth factor β in the radiation field. An immunologically mediated sporadic radiation pneumonitis occurs in about 10% of patients; bilateral alveolitis mediated by T cells results in infiltrates outside the radiation field. This form of radiation pneumonitis usually resolves without sequelae.


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InternalMed_Harrison. Pneumonia is a common problem in patients undergoing treatment for cancer. Bacterial pneumonia typically causes a localized infiltrate on chest radiographs. Therapy is tailored to the causative organism. When diffuse interstitial infiltrates appear in a febrile patient, the differential diagnosis is extensive and includes pneumonia due to infection with Pneumocystis carinii; viral infections including cytomegalovirus, adenovirus, herpes simplex virus, herpes zoster, respiratory syncytial virus, or intracellular pathogens such as Mycoplasma and Legionella; effects of drugs or radiation; tumor progression; nonspecific pneumonitis; and fungal disease. Detection of opportunistic pathogens in pulmonary infections is still a challenge. Diagnostic tools include chest radiographs, CT scans, bronchoscopy with bronchoalveolar lavage, brush cytology, transbronchial biopsy, fine-needle aspiration, and open lung biopsy. In addition to the culture, evaluation of bronchoalveolar lavage fluid for P.


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InternalMed_Harrison. with bronchoalveolar lavage, brush cytology, transbronchial biopsy, fine-needle aspiration, and open lung biopsy. In addition to the culture, evaluation of bronchoalveolar lavage fluid for P. carinii by polymerase chain reaction (PCR) and serum galactomannan test improve the diagnostic yield. Patients with cancer who are neutropenic and have fever and local infiltrates on chest radiograph should be treated initially with broad-spectrum antibiotics. A new or persistent focal infiltrate not responding to broad-spectrum antibiotics argues for initiation of empiric antifungal therapy. When diffuse bilateral infiltrates develop in patients with febrile neutropenia, broad-spectrum antibiotics plus trimethoprim-sulfamethoxazole, with or without erythromycin, should be initiated. Addition of an antiviral agent is necessary in some settings, such as patients undergoing allogeneic hematopoietic stem cell transplantation. If the patient does not improve in 4 days, open lung biopsy is the


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InternalMed_Harrison. of an antiviral agent is necessary in some settings, such as patients undergoing allogeneic hematopoietic stem cell transplantation. If the patient does not improve in 4 days, open lung biopsy is the procedure of choice. Bronchoscopy with bronchoalveolar lavage may be used in patients who are poor candidates for surgery.


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InternalMed_Harrison. In patients with pulmonary infiltrates who are afebrile, heart failure and multiple pulmonary emboli are in the differential diagnosis. Neutropenic enterocolitis (typhlitis) is the inflammation and necrosis of the cecum and surrounding tissues that may complicate the treatment FIGURE 331-5 Abdominal computed tomography (CT) scans of a 72-year-old woman with neutropenic enterocolitis secondary to chemotherapy. A. Air in inferior mesenteric vein (arrow) and bowel wall with pneumatosis intestinalis. B. CT scan of upper abdomen demonstrating air in portal vein (arrows).


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InternalMed_Harrison. of acute leukemia. Nevertheless, it may involve any segment of the gastrointestinal tract including small intestine, appendix, and colon. This complication has also been seen in patients with other forms of cancer treated with taxanes, 5-fluorouracil, irinotecan, vinorelbine, cisplatin, carboplatin, and high-dose chemotherapy (Fig. 331-5). It also has been reported in patients with AIDS, aplastic anemia, cyclic neutropenia, idiosyncratic drug reactions involving antibiotics, and immunosuppressive therapies. The patient develops right lower quadrant abdominal pain, often with rebound tenderness and a tense, distended abdomen, in a setting of fever and neutropenia. Watery diarrhea (often containing sloughed mucosa) and bacteremia are common, and bleeding may occur. Plain abdominal films are generally of little value in the diagnosis; CT scan may show marked bowel wall thickening, particularly in the cecum, with bowel wall edema, mesenteric stranding, and ascites, and may help to


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InternalMed_Harrison. are generally of little value in the diagnosis; CT scan may show marked bowel wall thickening, particularly in the cecum, with bowel wall edema, mesenteric stranding, and ascites, and may help to differentiate neutropenic colitis from other abdominal disorders such as appendicitis, diverticulitis, and Clostridium difficile–associated colitis in this high-risk population. Patients with bowel wall thickness >10 mm on ultrasonogram have higher mortality rates. However, bowel wall thickening is significantly more prominent in patients with C. difficile colitis. Pneumatosis intestinalis is a more specific finding, seen only in those with neutropenic enterocolitis and ischemia. The combined involvement of the small and large bowel suggests a diagnosis of neutropenic enterocolitis.


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InternalMed_Harrison. Rapid institution of broad-spectrum antibiotics, bowel rest, and nasogastric suction may reverse the process. Use of myeloid growth factors improved outcome significantly. Surgical intervention is reserved for severe cases of neutropenic enterocolitis with evidence of perforation, peritonitis, gangrenous bowel, or gastrointestinal hemorrhage despite correction of any coagulopathy. C. difficile colitis is increasing in incidence. Newer strains of C. difficile produce about 20 times more of toxins A and B compared to previously studied strains. C. difficile risk is also increased with chemotherapy. Antibiotic coverage for C. difficile should be added if pseudomembranous colitis cannot be excluded.


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InternalMed_Harrison. Hemorrhagic cystitis can develop in patients receiving cyclophosphamide or ifosfamide. Both drugs are metabolized to acrolein, which is a strong chemical irritant that is excreted in the urine. Prolonged contact or high concentrations may lead to bladder irritation and hemorrhage. Symptoms include gross hematuria, frequency, dysuria, burning, urgency, incontinence, and nocturia. The best management is prevention. Maintaining a high rate of urine flow minimizes exposure. In addition, 2-mercaptoethanesulfonate (mesna) detoxifies the metabolites and can be coadministered with the instigating drugs. Mesna usually is given three times on the day of ifosfamide administration in doses that are each 20% of the total ifosfamide dose. If hemorrhagic cystitis develops, the maintenance of a high urine flow may be sufficient supportive care. If conservative management is not effective, irrigation of the bladder with a 0.37–0.74% formalin solution for 10 min stops the bleeding in most cases.


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InternalMed_Harrison. urine flow may be sufficient supportive care. If conservative management is not effective, irrigation of the bladder with a 0.37–0.74% formalin solution for 10 min stops the bleeding in most cases. N-Acetylcysteine may also be an effective irrigant. Prostaglandin (carboprost) can inhibit the process. In extreme cases, ligation of the hypogastric arteries, urinary diversion, or cystectomy may be necessary.


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InternalMed_Harrison. Hemorrhagic cystitis also occurs in patients who undergo bone marrow transplantation (BMT). In the BMT setting, early-onset hemorrhagic cystitis is related to drugs in the treatment regimen (e.g., cyclophosphamide), and late-onset hemorrhagic cystitis is usually due to the polyoma virus BKV or adenovirus type 11. BKV load in urine alone or in combination with acute graft-versus-host disease correlates with development of hemorrhagic cystitis. Viral causes are usually detected by PCR-based diagnostic tests. Treatment of viral hemorrhagic cystitis is largely supportive, with reduction in doses of immunosuppressive agents, if possible. No antiviral therapy is approved, although cidofovir is reported to be effective in a small series. Hyperbaric oxygen therapy has been used successfully in patients with BKV-associated and cyclophosphamide-induced hemorrhagic cystitis during hematopoietic stem cell transplantation, as well as in hemorrhagic radiation cystitis.


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InternalMed_Harrison. Many antineoplastic drugs may cause hypersensitivity reaction. These reactions are unpredictable and potentially life-threatening. Most reactions occur during or within hours of parenteral drug administration. Taxanes, platinum compounds, asparaginase, etoposide, procarbazine, and biologic agents, including rituximab, bevacizumab, trastuzumab, gemtuzumab, cetuximab, and alemtuzumab, are more commonly associated with acute hypersensitivity reactions than are other agents. Acute hypersensitivity reactions to some drugs, such as taxanes, occur during the first or second dose administered. Hypersensitivity to platinum compounds occurs after prolonged exposure. Skin testing may identify patients with high risk for hypersensitivity after carboplatin exposure. Premedication with histamine H1 and H2 receptor antagonists and glucocorticoids reduces the incidence of hypersensitivity reaction to taxanes, particularly paclitaxel. Despite premedication, hypersensitivity reactions may still occur.


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InternalMed_Harrison. H2 receptor antagonists and glucocorticoids reduces the incidence of hypersensitivity reaction to taxanes, particularly paclitaxel. Despite premedication, hypersensitivity reactions may still occur. In these cases, rapid desensitization in the intensive care unit setting or re-treatment may be attempted with care, but the use of alternative agents may be required. Candidate patients for desensitization include those who have mild to severe hypersensitivity type I, with mast cell–mediated and IgE-dependent reactions occurring during a chemotherapy infusion or shortly thereafter.


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InternalMed_Harrison. 332e-1 Cellular and Molecular Biology of the Kidney Alfred L. George, Jr., Eric G. Neilson The kidney is one of the most highly differentiated organs in the body. At the conclusion of embryologic development, nearly 30 different cell types form a multitude of filtering capillaries and segmented nephrons secreted by adjacently developing podocytes. Epithelial podocytes facing the urinary space envelop the exterior basement membrane sup-porting these emerging endothelial capillaries. Podocytes are partially polarized and periodically fall off into the urinary space by epithelial-mesenchymal transition, and to a lesser extent apoptosis, only to be replenished by migrating parietal epithelia from Bowman capsule. Impaired replenishment results in heavy proteinuria. Podocytes attach to the basement membrane by special foot processes and share a slit-pore membrane with their neighbor. The slit-pore membrane forms a filter for plasma water and solute by the synthetic interaction of neph-332e


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InternalMed_Harrison. membrane by special foot processes and share a slit-pore membrane with their neighbor. The slit-pore membrane forms a filter for plasma water and solute by the synthetic interaction of neph-332e PaRT 13: Disorders of the Kidney and Urinary Tract enveloped by a dynamic interstitium. This cellular diversity modulates a variety of complex physiologic processes. Endocrine functions, the regulation of blood pressure and intraglomerular hemodynamics, solute and water transport, acid-base balance, and removal of drug metabolites are all accomplished by intricate mechanisms of renal response. This breadth of physiology hinges on the clever ingenuity of nephron architecture that evolved as complex organisms came out of water to live on land.


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InternalMed_Harrison. Kidneys develop from intermediate mesoderm under the timed or sequential control of a growing number of genes, described in Fig. 332e-1. The transcription of these genes is guided by morphogenic cues that invite two ureteric buds to each penetrate bilateral metanephric blastema, where they induce primary mesenchymal cells to form early nephrons. The two ureteric buds emerge from posterior nephric ducts and mature into separate collecting systems that eventually form a renal pelvis and ureter. Induced mesenchyme undergoes mesenchymal epithelial transitions to form comma-shaped bodies at the proximal end of each ureteric bud leading to the formation of S-shaped nephrons that cleft and enjoin with penetrating endothelial cells derived from sprouting angioblasts. Under the influence of vascular endothelial growth factor A (VEGF-A), these penetrating cells form capillaries with surrounding mesangial cells that differentiate into a glomerular filter for plasma water and solute. The ureteric


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InternalMed_Harrison. endothelial growth factor A (VEGF-A), these penetrating cells form capillaries with surrounding mesangial cells that differentiate into a glomerular filter for plasma water and solute. The ureteric buds branch, and each branch produce a new set of nephrons. The number of branching events ultimately determines the total number of nephrons in each kidney. There are approximately 900,000 glomeruli in each kidney in normal birth weight adults and as few as 225,000 in low-birth-weight adults, with the latter producing numerous comorbid risks.


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InternalMed_Harrison. Glomeruli evolve as complex capillary filters with fenestrated endothelia under the guiding influence of VEGF-A and angiopoietin-1 rin, annexin-4, CD2AP, FAT, ZO-1, P-cadherin, podocin, TRPC6, PLCE1, and Neph 1-3 proteins. Mutations in many of these proteins also result in heavy proteinuria. The glomerular capillaries are embedded in a mesangial matrix shrouded by parietal and proximal tubular epithelia forming Bowman capsule. Mesangial cells have an embryonic lineage consistent with arteriolar or juxtaglomerular cells and contain contractile actin-myosin fibers. These mesangial cells make contact with glomerular capillary loops, and their local matrix holds them in condensed arrangement.


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InternalMed_Harrison. Between nephrons lies the renal interstitium. This region forms a functional space surrounding glomeruli and their downstream tubules, which are home to resident and trafficking cells such as fibroblasts, dendritic cells, occasional lymphocytes, and lipid-laden macrophages. The cortical and medullary capillaries, which siphon off solute and water following tubular reclamation of glomerular filtrate, are also part of the interstitial fabric as well as a web of connective tissue that supports the kidney’s emblematic architecture of folding tubules. The relational precision of these structures determines the unique physiology of the kidney.


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InternalMed_Harrison. Each nephron is partitioned during embryologic development into a proximal tubule, descending and ascending limbs of the loop of Henle, distal tubule, and the collecting duct. These classic tubular segments build from subsegments lined by highly unique epithelia serving regional physiology. All nephrons have the same structural components, but there are two types whose structures depend on their location within the kidney. The majority of nephrons are cortical, with glomeruli located in the mid-to-outer cortex. Fewer nephrons are juxtamedullary, with glomeruli at the boundary of the cortex and outer medulla. Cortical nephrons have short loops of Henle, whereas juxtamedullary nephrons have long loops of Henle. There are critical differences in blood supply as well. The peritubular capillaries surrounding cortical nephrons are shared among adjacent nephrons. By contrast, juxtamedullary nephrons depend on individual capillaries Cellular and Molecular Biology of the Kidney


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InternalMed_Harrison. Cellular and Molecular Biology of the Kidney FIGuRE 332e-1 Genes controlling renal nephrogenesis. A growing number of genes have been identified at various stages of glomerulotubular development in the mammalian kidney. The genes listed have been tested in various genetically modified mice, and their location corresponds to the classical stages of kidney development postulated by Saxen in 1987. called vasa recta. Cortical nephrons perform most of the glomerular filtration because there are more of them and because their afferent arterioles are larger than their respective efferent arterioles. The juxtamedullary nephrons, with longer loops of Henle, create an osmotic gradient for concentrating urine. How developmental instructions specify the differentiation of all these unique epithelia among various tubular segments is still unknown.


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InternalMed_Harrison. Renal blood flow normally drains approximately 20% of the cardiac output, or 1000 mL/min. Blood reaches each nephron through the afferent arteriole leading into a glomerular capillary where large amounts of fluid and solutes are filtered to form the tubular fluid. The distal ends of the glomerular capillaries coalesce to form an efferent arteriole leading to the first segment of a second capillary network (cortical peritubular capillaries or medullary vasa recta) surrounding the tubules (Fig. 332e-2A). Thus, nephrons have two capillary beds arranged in a series separated by the efferent arteriole that regulates the hydrostatic pressure in both capillary beds. The distal capillaries empty into small venous branches that coalesce into larger veins to eventually form the renal vein.


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InternalMed_Harrison. The hydrostatic pressure gradient across the glomerular capillary wall is the primary driving force for glomerular filtration. Oncotic pressure within the capillary lumen, determined by the concentration of unfiltered plasma proteins, partially offsets the hydrostatic pressure gradient and opposes filtration. As the oncotic pressure rises along the length of the glomerular capillary, the driving force for filtration falls to zero on reaching the efferent arteriole. Approximately 20% of the renal plasma flow is filtered into Bowman space, and the ratio of glomerular filtration rate (GFR) to renal plasma flow determines the filtration fraction. Several factors, mostly hemodynamic, contribute to the regulation of filtration under physiologic conditions.


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InternalMed_Harrison. Although glomerular filtration is affected by renal artery pressure, this relationship is not linear across the range of physiologic blood pressures due to autoregulation of GFR. Autoregulation of glomerular filtration is the result of three major factors that modulate either afferent or efferent arteriolar tone: these include an autonomous vasoreactive (myogenic) reflex in the afferent arteriole, tubuloglomerular feedback, and angiotensin II-mediated vasoconstriction of the efferent arteriole. The myogenic reflex is a first line of defense against fluctuations in renal blood flow. Acute changes in renal perfusion pressure evoke reflex constriction or dilatation of the afferent arteriole in response to increased or decreased pressure, respectively. This phenomenon helps protect the glomerular capillary from sudden changes in systolic pressure.


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InternalMed_Harrison. Tubuloglomerular feedback (TGF) changes the rate of filtration and tubular flow by reflex vasoconstriction or dilatation of the afferent arteriole. TGF is mediated by specialized cells in the thick ascending limb of the loop of Henle called the macula densa that act as sensors of solute concentration and tubular flow rate. With high tubular flow rates, a proxy for an inappropriately high filtration rate, there is increased solute delivery to the macula densa (Fig. 332e-2B) that evokes vasoconstriction of the afferent arteriole causing GFR to return toward normal. One component of the soluble signal from the macula densa is adenosine triphosphate (ATP) released by the cells during increased NaCl reabsorption. ATP is metabolized in the extracellular space to generate adenosine, a potent vasoconstrictor of the afferent arteriole. During conditions associated with a fall in filtration rate, reduced solute delivery to the macula densa attenuates TGF, allowing afferent arteriolar dilatation


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InternalMed_Harrison. of the afferent arteriole. During conditions associated with a fall in filtration rate, reduced solute delivery to the macula densa attenuates TGF, allowing afferent arteriolar dilatation and restoring glomerular filtration to normal levels. Angiotensin II and reactive oxygen species enhance, while nitric oxide (NO) blunts, TGF.


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InternalMed_Harrison. The third component underlying autoregulation of GFR involves angiotensin II. During states of reduced renal blood flow, renin is released from granular cells within the wall of the afferent arteriole near the macula densa in a region called the juxtaglomerular apparatus (Fig. 332e-2B). Renin, a proteolytic enzyme, catalyzes the conversion of angiotensinogen to angiotensin I, which is subsequently converted to angiotensin II by angiotensin-converting enzyme (ACE) (Fig. 332e-2C). FIGuRE 332e-2 Renal microcirculation and the renin-angiotensin system. A. Diagram illustrating relationships of the nephron with glomerular and peritubular capillaries. B. Expanded view of the glomerulus with its juxtaglomerular apparatus including the macula densa and adjacent afferent arteriole. C. Proteolytic processing steps in the generation of angiotensins.


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InternalMed_Harrison. Angiotensin II evokes vasoconstriction of the efferent arteriole, and especially proteins mediating transport processes, provides the machin-332e-3 the resulting increased glomerular hydrostatic pressure elevates filtra-ery for directional movement of fluid and solutes by the nephron. tion to normal levels.


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InternalMed_Harrison. The renal tubules are composed of highly differentiated epithelia that vary dramatically in morphology and function along the nephron (Fig. 332e-3). The cells lining the various tubular segments form monolayers connected to one another by a specialized region of the adjacent lateral membranes called the tight junction. Tight junctions form an occlusive barrier that separates the lumen of the tubule from the interstitial spaces surrounding the tubule and also apportions the cell membrane into discrete domains: the apical membrane facing the tubular lumen and the basolateral membrane facing the interstitium. This regionalization allows cells to allocate membrane proteins and lipids asymmetrically. Owing to this feature, renal epithelial cells are said to be polarized. The asymmetric assignment of membrane proteins, There are two types of epithelial transport. Movement of fluid and solutes sequentially across the apical and basolateral cell membranes (or vice versa) mediated by


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InternalMed_Harrison. assignment of membrane proteins, There are two types of epithelial transport. Movement of fluid and solutes sequentially across the apical and basolateral cell membranes (or vice versa) mediated by transporters, channels, or pumps is called cellular transport. By contrast, movement of fluid and solutes through the narrow passageway between adjacent cells is called paracellular transport. Paracellular transport occurs through tight junctions, indicating that they are not completely “tight.” Indeed, some epithelial cell layers allow rather robust paracellular transport to occur (leaky epithelia), whereas other epithelia have more effective tight junctions (tight epithelia). In addition, because the ability of ions to flow through the paracellular pathway determines the electrical resistance across the epithelial monolayer, leaky and tight epithelia are also referred to as lowor high-resistance epithelia, respectively. The proximal tubule


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InternalMed_Harrison. Chapter 332e Cellular and Molecular Biology of the Kidney H2O, solutes


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InternalMed_Harrison. FIGuRE 332e-3 Transport activities of the major nephron segments. Representative cells from five major tubular segments are illustrated with the lumen side (apical membrane) facing left and interstitial side (basolateral membrane) facing right. A. Proximal tubular cells. B. Typical cell in the thick ascending limb of the loop of Henle. C. Distal convoluted tubular cell. D. Overview of entire nephron. E. Cortical collecting duct cells. F. Typical cell in the inner medullary collecting duct. The major membrane transporters, channels, and pumps are drawn with arrows indicating the direction of solute or water movement. For some events, the stoichiometry of transport is indicated by numerals preceding the solute. Targets for major diuretic agents are labeled. The actions of hormones are illustrated by arrows with plus signs for stimulatory effects and lines with perpendicular ends for inhibitory events. Dotted lines indicate free diffusion across cell membranes. The dashed line indicates


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InternalMed_Harrison. by arrows with plus signs for stimulatory effects and lines with perpendicular ends for inhibitory events. Dotted lines indicate free diffusion across cell membranes. The dashed line indicates water impermeability of cell membranes in the thick ascending limb and distal convoluted tubule.


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InternalMed_Harrison. Lumen Interstitium 3NaThiazidesDISTAL CONVOLUTED TUBULE H2OCa2KClNaClCa3NaC+ Ca, Mg 3Na Loop diuretics THICK ASCENDING LIMB BCa H2O K 2K Cl Na 2Cl K Chapter 332e Cellular and Molecular Biology of the Kidney Loop of Henle: contains leaky epithelia, whereas distal nephron segments, such as the collecting duct, contain tight epithelia. Leaky epithelia are most well suited for bulk fluid reabsorption, whereas tight epithelia allow for more refined control and regulation of transport.


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InternalMed_Harrison. Cell membranes are composed of hydrophobic lipids that repel water and aqueous solutes. The movement of solutes and water across cell membranes is made possible by discrete classes of integral membrane proteins, including channels, pumps, and transporters. These different mechanisms mediate specific types of transport activities, including active transport (pumps), passive transport (channels), facilitated diffusion (transporters), and secondary active transport (cotransporters). Active transport requires metabolic energy generated by the hydrolysis of ATP. Active transport pumps are ion-translocating ATPases, including the ubiquitous Na+/K+-ATPase, the H+-ATPases, and Ca2+-ATPases. Active transport creates asymmetric ion concentrations across a cell membrane and can move ions against a chemical gradient. The potential energy stored in a concentration gradient of an ion such as Na+ can be used to drive transport through other mechanisms (secondary active transport). Pumps are often


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InternalMed_Harrison. chemical gradient. The potential energy stored in a concentration gradient of an ion such as Na+ can be used to drive transport through other mechanisms (secondary active transport). Pumps are often electrogenic, meaning they can create an asymmetric distribution of electrostatic charges across the membrane and establish a voltage or membrane potential. The movement of solutes through a membrane protein by simple diffusion is called passive transport. This activity is mediated by channels created by selectively permeable membrane proteins, and it allows solute or water to move across a membrane driven by favorable concentration gradients or electrochemical potential. Facilitated diffusion is a specialized type of passive transport mediated by simple transporters called carriers or uniporters. For example, hexose transporters such as GLUT2 mediate glucose transport by tubular cells. These transporters are driven by the concentration gradient for glucose that is highest in extracellular


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InternalMed_Harrison. For example, hexose transporters such as GLUT2 mediate glucose transport by tubular cells. These transporters are driven by the concentration gradient for glucose that is highest in extracellular fluids and lowest in the cytoplasm due to rapid metabolism. Many other transporters operate by translocating two or more ions/solutes in concert either in the same direction (symporters or cotransporters) or in opposite directions (antiporters or exchangers) across the cell membrane. The movement of two or more ions/solutes may produce no net change in the balance of electrostatic charges across the membrane (electroneutral), or a transport event may alter the balance of charges (electrogenic). Several inherited disorders of renal tubular solute and water transport occur as a consequence of mutations in genes encoding a variety of channels, transporter proteins, and their regulators (Table 332e-1).


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InternalMed_Harrison. Each anatomic segment of the nephron has unique characteristics and specialized functions enabling selective transport of solutes and water (Fig. 332e-3). Through sequential events of reabsorption and secretion along the nephron, tubular fluid is progressively conditioned into urine. Knowledge of the major tubular mechanisms responsible for solute and water transport is critical for understanding hormonal regulation of kidney function and the pharmacologic manipulation of renal excretion. The proximal tubule is responsible for reabsorbing ~60% of filtered NaCl and water, as well as ~90% of filtered bicarbonate and most critical nutrients such as glucose and amino acids. The proximal tubule uses both cellular and paracellular transport mechanisms. The apical membrane of proximal tubular cells has an expanded surface area available for reabsorptive work created by a dense array of microvilli called the brush border, and leaky tight junctions enable high-capacity fluid reabsorption.


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InternalMed_Harrison. Solute and water pass through these tight junctions to enter the lateral intercellular space where absorption by the peritubular capillaries occurs. Bulk fluid reabsorption by the proximal tubule is driven by high oncotic pressure and low hydrostatic pressure within the peritubular capillaries. Cellular transport of most solutes by the proximal tubule is coupled to the Na+ concentration gradient established by the activity of a basolateral Na+/K+-ATPase (Fig. 332e-3A). This active transport mechanism maintains a steep Na+ gradient by keeping intracellular Na+ concentrations low. Solute reabsorption is coupled to the Na+ gradient by Na+-dependent transporters such as Na+-glucose and Na+-phosphate cotransporters. In addition to the paracellular route, water reabsorption also occurs through the cellular pathway enabled by constitutively active water channels (aquaporin-1) present on both apical and basolateral membranes.


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InternalMed_Harrison. Proximal tubular cells reclaim bicarbonate by a mechanism dependent on carbonic anhydrases. Filtered bicarbonate is first titrated by protons delivered to the lumen by Na+/H+ exchange. The resulting carbonic acid (H2CO3) is metabolized by brush border carbonic anhydrase to water and carbon dioxide. Dissolved carbon dioxide then diffuses into the cell, where it is enzymatically hydrated by cytoplasmic carbonic anhydrase to re-form carbonic acid. Finally, intracellular carbonic acid dissociates into free protons and bicarbonate anions, and bicarbonate exits the cell through a basolateral Na+/HCO3− cotransporter. Chapter 332e Cellular and Molecular Biology of the Kidney aOnline Mendelian Inheritance in Man database (http://www.ncbi.nlm.nih.gov/Omim).


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InternalMed_Harrison. Chapter 332e Cellular and Molecular Biology of the Kidney aOnline Mendelian Inheritance in Man database (http://www.ncbi.nlm.nih.gov/Omim). This process is saturable, resulting in urinary bicarbonate excretion Filtered hydrogen phosphate ion (HPO42-) is also titrated in the proxiwhen plasma levels exceed the physiologically normal range (24-26 mal tubule by secreted H+ to form H2PO4 -, and this reaction constitutes meq/L). Carbonic anhydrase inhibitors such as acetazolamide, a class a major component of the urinary buffer referred to as titratable acid. of weak diuretic agents, block proximal tubule reabsorption of bicar-Most filtered phosphate ion is reabsorbed by the proximal tubule bonate and are useful for alkalinizing the urine. through a sodium-coupled cotransport process that is regulated by


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InternalMed_Harrison. The proximal tubule contributes to acid secretion by two mecha-parathyroid hormone. nisms involving the titration of the urinary buffers ammonia (NH3) Chloride is poorly reabsorbed throughout the first segment of the and phosphate. Renal NH3 is produced by glutamine metabolism in proximal tubule, and a rise in Cl− concentration counterbalances the the proximal tubule. Subsequent diffusion of NH3 out of the proxi-removal of bicarbonate anion from tubular fluid. In later proximal mal tubular cell enables trapping of H+ secreted by sodium-proton tubular segments, cellular Cl− reabsorption is initiated by apical exchange in the lumen as ammonium ion (NH4+). Cellular K+ levels exchange of cellular formate for higher luminal concentrations of inversely modulate proximal tubular ammoniagenesis, and in the Cl-. Once in the lumen, formate anions are titrated by H+ (provided setting of high serum K+ from hypoaldosteronism, reduced ammo-by Na+/H+ exchange) to generate neutral formic acid, which


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InternalMed_Harrison. and in the Cl-. Once in the lumen, formate anions are titrated by H+ (provided setting of high serum K+ from hypoaldosteronism, reduced ammo-by Na+/H+ exchange) to generate neutral formic acid, which can difniagenesis facilitates the appearance of type IV renal tubular acidosis. fuse passively across the apical membrane back into the cell where it dissociates a proton and is recycled. Basolateral Cl− exit is mediated by a K+/Cl− cotransporter.