2273 Nervous System Disorders in Critical Care CHAPTER 307

centrally acting α2

 agonist dexmedetomidine may reduce delirium and

shorten the duration of mechanical ventilation compared to the use

of benzodiazepines such as lorazepam or midazolam. The presence of

family members in the ICU may also help to calm and orient agitated

patients, and in severe cases, low doses of neuroleptics (e.g., haloperidol 0.5–1 mg) can be useful. Current strategies focus on limiting the

use of sedative medications when this can be done safely.

In the ICU setting, several metabolic causes of an altered level of

consciousness predominate. Hypercarbic encephalopathy can present

with headache, confusion, stupor, or coma. Hypoventilation syndrome

occurs most frequently in patients with a history of chronic CO2

retention who are receiving oxygen therapy for emphysema or chronic

pulmonary disease (Chap. 296). The elevated Paco2

 leading to CO2

narcosis may have a direct anesthetic effect, and cerebral vasodilation

from increased Paco2

 can lead to increased ICP. Hepatic encephalopathy is suggested by asterixis and can occur in chronic liver failure or

acute fulminant hepatic failure. Both hyperglycemia and hypoglycemia

can cause encephalopathy, as can hypernatremia and hyponatremia.

Confusion, impairment of eye movements, and gait ataxia are the hallmarks of acute Wernicke’s disease (see below).

■ SEPSIS-ASSOCIATED ENCEPHALOPATHY

Pathogenesis In patients with sepsis, the systemic response to

infectious agents leads to the release of circulating inflammatory mediators that appear to contribute to encephalopathy. Critical illness, in

association with the systemic inflammatory response syndrome (SIRS),

can lead to multisystem organ failure. This syndrome can occur in the

setting of apparent sepsis, severe burns, or trauma, even without clear

identification of an infectious agent. Many patients with critical illness,

sepsis, or SIRS develop encephalopathy without obvious explanation.

This condition is broadly termed sepsis-associated encephalopathy.

Although the specific mediators leading to neurologic dysfunction

remain uncertain, it is clear that the encephalopathy is not simply the

result of metabolic derangements of multiorgan failure. The cytokines

tumor necrosis factor, interleukin (IL) 1, IL-2, and IL-6 are thought to

play a role in this syndrome.

Diagnosis Sepsis-associated encephalopathy presents clinically as

a diffuse dysfunction of the brain without prominent focal findings.

Confusion, disorientation, agitation, and fluctuations in level of alertness are typical. In more profound cases, especially with hemodynamic

compromise, the decrease in level of alertness can be more prominent,

at times resulting in coma. Hyperreflexia and frontal release signs

such as a grasp or snout reflex (Chap. 30) can be seen. Abnormal

movements such as myoclonus, tremor, or asterixis can occur. Sepsisassociated encephalopathy is quite common, occurring in the majority

of patients with sepsis and multisystem organ failure. Diagnosis is often

difficult because of the multiple potential causes of neurologic dysfunction in critically ill patients and requires exclusion of structural, metabolic, toxic, and infectious (e.g., meningitis or encephalitis) causes. The

mortality rate of patients with sepsis-associated encephalopathy severe

enough to produce coma approaches 50%, although this principally

reflects the severity of the underlying critical illness and is generally

not a direct result of the encephalopathy. Patients dying from severe

sepsis or septic shock may have elevated levels of the serum brain

injury biomarker S-100β and neuropathologic findings of neuronal

apoptosis and cerebral ischemic injury. Successful treatment of the

underlying critical illness almost always results in substantial improvement of the encephalopathy. However, although severe disability to the

level of chronic unresponsive wakeful or minimally conscious states

is uncommon, long-term cognitive dysfunction clinically similar to

dementia is being increasingly recognized in some survivors, especially

in older patients.

■ OSMOTIC DEMYELINATION SYNDROME

(CENTRAL PONTINE MYELINOLYSIS)

This disorder often presents in a devastating fashion as quadriplegia

and pseudobulbar palsy, although less severe presentations may occur.

Predisposing factors include severe underlying medical illness or

nutritional deficiency; most cases are associated with rapid correction

of hyponatremia or with hyperosmolar states, and clinical symptoms

are usually identified a few days after sodium correction. Previously

termed central pontine myelinolysis, the more accurate term osmotic

demyelination syndrome is now preferred. The pathology consists of

demyelination without inflammation in the base of the pons, with relative sparing of axons and nerve cells. MRI is useful in establishing the

diagnosis (Fig. 307-5) and may also identify partial forms that present

as confusion, dysarthria, and/or disturbances of conjugate gaze without quadriplegia. Occasional cases present with lesions outside of the

brainstem. Therapy for the restoration of severe hyponatremia should

aim for gradual correction, i.e., by ≤8 mmol/L (8 meq/L) within 24 h

and 15 mmol/L (15 meq/L) within 48 h.

■ WERNICKE’S DISEASE

Wernicke’s disease is a common and preventable disorder due to a deficiency of thiamine (Chap. 333). In the United States, alcoholics account

for most cases, but patients with malnutrition due to hyperemesis, starvation, renal dialysis, cancer, HIV/AIDS, or rarely gastric surgery are

also at risk. The characteristic clinical triad is ophthalmoplegia, ataxia,

and global confusion. However, only one-third of patients with acute

Wernicke’s disease present with the classic clinical triad. Most patients

are profoundly disoriented, indifferent, and inattentive, although rarely

they have an agitated delirium related to ethanol withdrawal. If the disease is not treated, stupor, coma, and death may ensue. Ocular motor

abnormalities include horizontal nystagmus on lateral gaze, lateral

rectus palsy (usually bilateral), conjugate gaze palsies, and rarely ptosis.

Gait ataxia probably results from a combination of polyneuropathy,

cerebellar involvement, and vestibular paresis. The pupils are usually

spared, but they may become miotic with advanced disease.

Wernicke’s disease is usually associated with other manifestations

of nutritional disease, such as polyneuropathy. Rarely, amblyopia or

myelopathy occurs. Tachycardia and postural hypotension may be

related to impaired function of the autonomic nervous system or to

the coexistence of cardiovascular beriberi. Patients who recover show

improvement in ocular palsies within hours after the administration

of thiamine, but horizontal nystagmus may persist. Ataxia improves

more slowly than the ocular motor abnormalities. Approximately half

recover incompletely and are left with a slow, shuffling, wide-based gait

and an inability to tandem walk. Apathy, drowsiness, and confusion

improve more gradually. As these symptoms recede, an amnestic state

with impairment in recent memory and learning may become more

apparent (Korsakoff’s psychosis). Korsakoff ’s psychosis is frequently

FIGURE 307-5 Osmotic demyelination syndrome. Axial T2-weighted magnetic

resonance scan through the pons reveals a symmetric area of abnormal high signal

intensity within the basis pontis (arrows).

2274 PART 8 Critical Care Medicine

persistent; the residual mental state is characterized by gaps in memory,

confabulation, and disordered temporal sequencing.

Pathology Periventricular lesions surround the third ventricle,

aqueduct, and fourth ventricle, with petechial hemorrhages in occasional acute cases and atrophy of the mammillary bodies in most

chronic cases. There is frequently endothelial proliferation, demyelination, and some neuronal loss. These changes may be detected by MRI

(Fig. 307-6). The amnestic defect is related to lesions in the dorsal

medial nuclei of the thalamus.

Pathogenesis Thiamine is a cofactor of several enzymes, including

transketolase, pyruvate dehydrogenase, and α-ketoglutarate dehydrogenase. Thiamine deficiency produces a diffuse decrease in cerebral

glucose utilization and results in mitochondrial damage. Glutamate

accumulates due to impairment of α-ketoglutarate dehydrogenase

activity and, in combination with the energy deficiency, may result in

excitotoxic cell damage.

TREATMENT

Wernicke’s Disease

Wernicke’s disease is a medical emergency and requires immediate

administration of high-dose thiamine, in a dose of 500 mg IV. The

dose should be begun prior to treatment with IV glucose solutions

and continued three times daily for 2–3 days. Thiamine may then

be given in a dose of 250 mg IV or IM daily for 5 more days (in

conjunction with other B vitamins), with oral thiamine then continued at 100 mg daily until the patient is no longer considered at risk.

Glucose infusions may precipitate Wernicke’s disease in a previously

unaffected patient or cause a rapid worsening of an early form of

the disease. For this reason, thiamine should be administered to all

alcoholic patients requiring parenteral glucose.

■ HYPERPERFUSION DISORDERS (POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME)

Several seemingly diverse syndromes including hypertensive encephalopathy, eclampsia, postcarotid endarterectomy syndrome, and toxicity

from calcineurin inhibitor and other medications share the common

pathogenesis of hyperperfusion likely due to endothelial dysfunction.

Vasogenic edema is typically the primary process leading to neurologic

dysfunction, and this is thought to result from one of two mechanisms:

exceeding the cerebral autoregulatory threshold leading to increased

CBF and capillary leakage into the interstitium, or direct impairment

of the BBB itself. The predilection of all of the hyperperfusion disorders

to affect the posterior rather than anterior portions of the brain may

be due to a lower threshold for autoregulatory breakthrough in the

posterior circulation or a vasculopathy that is more common in these

blood vessels.

These disorders of hyperperfusion can be divided into those caused

primarily by increased pressure and those due to endothelial dysfunction from a toxic or autoimmune etiology (Table 307-3). In reality,

both of these processes likely play some role in each of these disorders.

The clinical presentation of all of the hyperperfusion syndromes is similar with prominent headaches, seizures, or focal neurologic deficits.

Headaches have no specific characteristics, range from mild to severe,

and may be accompanied by alterations in consciousness ranging

from confusion to coma. Seizures may be present, and these can be of

multiple types depending on the severity and location of the edema.

Nonconvulsive seizures have been described in hyperperfusion states;

therefore, a low threshold for obtaining an electroencephalogram

(EEG) in these patients should be maintained. The typical focal deficit

in hyperperfusion states is cortical visual loss, given the tendency of

the process to involve the occipital lobes. However, any focal deficit can

occur depending on the area affected, as evidenced by patients who,

after carotid endarterectomy, exhibit neurologic dysfunction referable

to the ipsilateral newly reperfused hemisphere. It appears as if the

rapidity of rise, rather than the absolute value of pressure, is the most

important risk factor.

MRI classically exhibits the high T2 signal of edema primarily in the

posterior occipital lobes, not respecting any single vascular territory

(Fig. 307-7). CT is less sensitive but may show a pattern of patchy

hypodensity in the involved territory. The term posterior reversible

TABLE 307-3 Common Etiologies of Posterior Reversible

Encephalopathy Syndrome

Disorders in which increased capillary pressure dominates the pathophysiology

 Hypertensive encephalopathy, including secondary causes such as

renovascular hypertension, pheochromocytoma, cocaine use, etc.

Postcarotid endarterectomy syndrome

Preeclampsia/eclampsia

Disorders in which endothelial dysfunction dominates the pathophysiology

Calcineurin inhibitor toxicity (e.g., cyclosporine, tacrolimus)

 Chemotherapeutic agent toxicity (e.g., cytarabine, azathioprine, 5-fluorouracil,

cisplatin, methotrexate, tumor necrosis factor α antagonists)

HELLP syndrome (hemolysis, elevated liver enzyme levels, low platelet count)

Hemolytic-uremic syndrome (HUS)

FIGURE 307-7 Axial fluid-attenuated inversion recovery (FLAIR) magnetic

resonance imaging (MRI) of the brain in a patient taking cyclosporine after liver

transplantation, who presented with seizures, headache, and cortical blindness.

Increased signal is seen bilaterally in the occipital lobes predominantly involving

the white matter, consistent with a hyperperfusion state secondary to calcineurin

inhibitor exposure.

FIGURE 307-6 Wernicke’s disease. Coronal T1-weighted postcontrast magnetic

resonance imaging reveals abnormal enhancement of the mammillary bodies

(arrows), typical of acute Wernicke’s encephalopathy.

2275 Nervous System Disorders in Critical Care CHAPTER 307

encephalopathy syndrome (PRES) is often used to describe these conditions; however, the clinical syndrome is not always reversible or limited

just to the posterior brain regions. Vessel imaging may demonstrate

narrowing of the cerebral vasculature, especially in the posterior circulation; whether this noninflammatory vasculopathy is a primary cause

of the edema or occurs as a secondary phenomenon remains unclear.

Other ancillary studies such as CSF analysis often yield nonspecific

results. Many of the substances that have been implicated, such as

cyclosporine, can cause this syndrome even at low doses or after years

of treatment. Therefore, normal serum levels of these medications do

not exclude them as inciting agents.

Treatment involves judicious lowering of the blood pressure with

IV agents such as labetalol or nicardipine, removal of the offending

medication, and treatment of an underlying medical condition such

as eclampsia. If the blood pressure is very elevated, it is reasonable to

lower the MAP by ~20% initially, as further lowering of the pressure

may cause secondary ischemia and possibly infarction as pressure

drops below the lower range of the patient’s autoregulatory capability.

Seizures must be identified and controlled, often necessitating continuous EEG monitoring. Anticonvulsants are effective when seizure activity is identified, but in the special case of eclampsia, there is evidence to

support the use of magnesium sulfate for seizure control.

■ POST–SOLID ORGAN TRANSPLANT BRAIN INJURY

Immunosuppressive medications are administered in high doses to

patients after solid organ transplant, and many of these compounds

have well-described neurologic complications. In patients with headache, seizures, or focal neurologic deficits taking calcineurin inhibitors,

the diagnosis of hyperperfusion syndrome should be considered, as

discussed above. This neurotoxicity occurs mainly with cyclosporine

and tacrolimus and can present even in the setting of normal serum

drug levels. Treatment primarily involves lowering the drug dosage

or discontinuing the drug. Sirolimus has very few recorded cases of

neurotoxicity and may be a reasonable alternative for some patients.

Other examples of immunosuppressive medications and their neurologic complications include OKT3-associated akinetic mutism and

the leukoencephalopathy seen with methotrexate, especially when it

is administered intrathecally or with concurrent radiotherapy. In any

solid organ transplant patient with neurologic complaints, a careful

examination of the medication list is required to search for these possible drug effects.

Cerebrovascular complications of solid organ transplant are often

first recognized in the immediate postoperative period. Border zone

territory infarctions can occur, especially in the setting of systemic

hypotension during cardiac transplant surgery. Embolic infarctions

classically complicate cardiac transplantation, but all solid organ transplant procedures place patients at risk for systemic emboli. When cerebral embolization accompanies renal or liver transplantation surgery,

a careful search for right-to-left shunting should include evaluation of

the heart with agitated saline echocardiography (i.e., “bubble study”),

as well as looking for intrapulmonary shunting. Renal and some cardiac transplant patients often have advanced atherosclerosis, providing a risk for stroke. Imaging with CT or MRI should be done when

cerebrovascular complications are suspected to confirm the diagnosis

and to exclude intracerebral hemorrhage, which most often occurs in

the setting of coagulopathy secondary to liver failure or after cardiac

bypass procedures.

Given that patients with solid organ transplants are chronically

immunosuppressed, infections are a common concern (Chap. 143).

In any transplant patient with new CNS signs or symptoms such as

seizure, confusion, or focal deficit, the diagnosis of a CNS infection

should be considered and evaluated through imaging (usually MRI)

and possibly LP. The most common pathogens responsible for CNS

infections in these patients vary based on time since transplant. In

the first month posttransplant, common pathogens include the usual

bacterial organisms associated with surgical procedures and indwelling

catheters. Starting in the second month posttransplant, opportunistic

infections of the CNS become more common, including Nocardia and

Toxoplasma species as well as fungal infections such as aspergillosis.

Viral infections that can affect the brain of the immunosuppressed

patient, such as herpes simplex virus, cytomegalovirus, human herpesvirus type 6 (HHV-6), and varicella, also become more common

after the first month posttransplant. Beyond 6 months, immunosuppressed posttransplant patients still remain at risk for these opportunistic bacterial, fungal, and viral infections but can also suffer late CNS

infectious complications such as progressive multifocal leukoencephalopathy (PML) associated with JC virus (Chap. 137) and Epstein-Barr

virus–driven clonal expansions of B cells resulting in posttransplant

lymphoproliferative disorder or CNS lymphoma (Chap. 90).

CNS COMPLICATIONS OF CHECKPOINT

INHIBITOR AND CHIMERIC ANTIGEN

RECEPTOR T-CELL THERAPY

Cancer immunotherapy is now a widely used treatment for both solid

tumors and hematologic malignances. Two types of this immunotherapy, checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell

(CAR-T) therapy, can carry significant neurologic toxicity that may

manifest as encephalopathy, cerebral edema, or white matter demyelination. These complications may be severe and require neurocritical

care evaluation and intervention.

Immune checkpoint inhibitors are monoclonal antibodies that bind

to normally occurring checkpoint proteins such as PD-1, PD-L1, and

CTLA-4, thereby freeing T cells to attack cancerous cells. Currently

available checkpoint inhibitors include pembrolizumab, nivolumab,

cemiplimab, atezolizumab, avelumab, durvalumab, and ipilimumab.

Common side effects are diarrhea, rash, and pneumonitis. Neurologic

side effects occur in ~5% of patients treated with monotherapy and

~10% undergoing combination therapy, presumably as a result of

shared antigens between tumor cells and self, leading to an autoimmune process. CNS adverse events include limbic encephalitis, cerebellitis, and myelitis. A clinical syndrome of encephalopathy, memory

disturbances, and seizures may occur. Peripheral nervous system

complications such as myasthenia gravis, myositis, and neuropathy

have also been described and may be even more common than CNS

manifestations.

Patients who develop CNS neurologic symptoms while on checkpoint inhibitor treatment should undergo MRI studies of the brain or

spinal cord, based on clinical symptoms. Mesial temporal lobe hyperintensities and a lymphocytic CSF pleocytosis may be present. EEG

may be appropriate to evaluate for subclinical seizures. Various autoantibodies such as anti-Ma2, anti-GFAP, anti-Hu, and anti-CASPR2

have been described but are not required for diagnosis. Treatment

consists of discontinuing the checkpoint inhibitor and administering

high-dose corticosteroids. Intravenous immunoglobulins and plasmapheresis have been used in severe cases. For mild cases, restarting the

checkpoint inhibitor may be considered; however, relapse with fatal

necrotizing encephalitis has been described. Given that checkpoint

inhibitor–treated patients are immunocompromised, before checkpoint

inhibitor–related neurotoxicity is diagnosed, it is imperative to rule out

an alternative diagnosis such as cerebral metastases, infection, or stroke.

CAR-T therapy for leukemia or lymphoma involves removing a

patient’s T cells and genetically engineering them using a disarmed

virus to produce surface chimeric antigen receptors that, when given

back to the patient, recognize antigens on tumor cells. CAR-T therapy

is frequently associated with significant side effects, which usually

occur as either cytokine release syndrome (CRS) or neurotoxicity.

These two types of CAR-T side effects are distinct but often occur in

the same patient, and both occur within days of initiation of CAR-T

treatment. CRS is a clinical syndrome of hypotension, fever, and

hypoxia, which may have associated multiorgan dysfunction. CRS

occurs in 80–100% of CAR-T–treated patients and is due to widespread release of proinflammatory cytokines. Treatment is with the

IL-6 receptor pathway blocker tocilizumab, which can alleviate CRS

symptoms without impairing the antitumor efficacy of the CAR-T

cells; corticosteroids may also be administered.

CAR-T neurotoxicity is less common but still occurs in more than

half of treated patients. Clinical manifestations may include headache,

2276 PART 8 Critical Care Medicine

encephalopathy, aphasia, seizures, tremors, and life-threatening cerebral edema. Predictors of occurrence of neurotoxicity include earlier

and more severe CRS, fever, elevated C-reactive protein and serum

ferritin, and older patient age. Treatment of CAR-T neurotoxicity also

involves administration of tocilizumab (as most of these patients also

have CRS) and corticosteroids. In addition to these treatments, patients

with CAR-T neurotoxicity should also undergo brain imaging and EEG

if indicated based on symptoms, with concurrent treatment of cerebral

edema and seizures if present.

CRITICAL CARE DISORDERS OF THE

PERIPHERAL NERVOUS SYSTEM

Critical illness with disorders of the PNS arises in two contexts: (1)

primary neurologic diseases that require critical care interventions

such as intubation and mechanical ventilation, and (2) secondary PNS

manifestations of systemic critical illness, often involving multisystem

organ failure. The former include acute polyneuropathies such as

Guillain-Barré syndrome (Chap. 447), neuromuscular junction disorders including myasthenia gravis (Chap. 448) and botulism (Chap.

153), and primary muscle disorders such as polymyositis (Chap. 365).

The latter result either from the systemic disease itself or as a consequence of interventions and as a group are often referred to as ICUacquired weakness (ICUAW).

General principles of respiratory evaluation in patients with PNS

involvement, regardless of cause, include assessment of pulmonary

mechanics, such as maximal inspiratory force (MIF) and vital capacity

(VC), and evaluation of strength of bulbar muscles. Regardless of the

cause of weakness, endotracheal intubation should be considered when

the MIF falls to below –25 cmH2

O or the VC is <1 L. Also, patients

with severe palatal weakness may require endotracheal intubation in

order to prevent acute upper airway obstruction or recurrent aspiration. Arterial blood gases and oxygen saturation from pulse oximetry

are used to follow patients with potential respiratory compromise

from PNS dysfunction. However, intubation and mechanical ventilation should be undertaken based on clinical assessment rather than

waiting until oxygen saturation drops or CO2

 retention develops from

hypoventilation. Noninvasive mechanical ventilation may be considered initially in lieu of endotracheal intubation in myasthenia gravis

but is generally insufficient in patients with severe bulbar weakness or

ventilatory failure with hypercarbia. Principles of mechanical ventilation are discussed in Chap. 302.

■ NEUROPATHY

Although encephalopathy may be the most obvious neurologic dysfunction in critically ill patients, dysfunction of the PNS is also quite

common. It is typically present in patients with prolonged critical

illnesses lasting several weeks and involving sepsis; clinical suspicion

is aroused when there is failure to wean from mechanical ventilation

despite improvement of the underlying sepsis and critical illness.

Critical illness polyneuropathy refers to the most common PNS complication related to critical illness; it is seen in the setting of prolonged

critical illness, sepsis, and multisystem organ failure. Neurologic findings include diffuse weakness, decreased reflexes, and distal sensory

loss. Electrophysiologic studies demonstrate a diffuse, symmetric,

distal axonal sensorimotor neuropathy, and pathologic studies have

confirmed axonal degeneration. The precise mechanism of critical

illness polyneuropathy remains unclear, but circulating factors such

as cytokines, which are associated with sepsis and SIRS, are thought

to play a role. It has been reported that up to 70% of patients with the

sepsis syndrome have some degree of neuropathy, although far fewer

have a clinical syndrome profound enough to cause severe respiratory muscle weakness requiring prolonged mechanical ventilation or

resulting in failure to wean. Aggressive glycemic control with insulin

infusions appears to decrease the risk of critical illness polyneuropathy.

Treatment is otherwise supportive, with specific intervention directed

at treating the underlying illness. Although spontaneous recovery is

usually seen, the time course may extend over weeks to months and

necessitate long-term ventilatory support and care even after the

underlying critical illness has resolved.

■ DISORDERS OF NEUROMUSCULAR

TRANSMISSION

A defect in neuromuscular transmission may be a source of weakness

in critically ill patients. Botulism (Chap. 153) may be acquired by

ingesting botulinum toxin from improperly stored food or may arise

from an anaerobic abscess from Clostridium botulinum (wound botulism). Infants can present with generalized weakness from gut-derived

Clostridium infection, especially if they are fed honey. Diplopia and

dysphagia are early signs of food-borne botulism. Treatment is mostly

supportive, although use of antitoxin early in the course may limit the

duration of the neuromuscular blockade. General ICU care is similar

to patients with Guillain-Barré syndrome or myasthenia gravis with

focused care to avoid ulcer formation at pressure points, deep venous

thromboprophylaxis, and infection prevention. Public health officers

should be rapidly informed when the diagnosis is made to prevent

further exposure to others from the tainted food or source of wound

botulism (such as injection drug use).

Undiagnosed myasthenia gravis (Chap. 448) may be a consideration in weak ICU patients; however, persistent weakness secondary

to impaired neuromuscular junction transmission is almost always

due to administration of drugs. A number of medications impair neuromuscular transmission; these include antibiotics, especially aminoglycosides, and beta-blocking agents. In the ICU, the nondepolarizing

neuromuscular blocking agents (nd-NMBAs), also known as muscle

relaxants, are most commonly responsible. Included in this group of

drugs are such agents as pancuronium, vecuronium, rocuronium, and

cisatracurium. They are often used to facilitate mechanical ventilation

or other critical care procedures, but with prolonged use, persistent

neuromuscular blockade may result in weakness even after discontinuation of these agents hours or days earlier. Risk factors for this

prolonged action of neuromuscular blocking agents include female sex,

metabolic acidosis, and renal failure.

Prolonged neuromuscular blockade does not appear to produce

permanent damage to the PNS. Once the offending medications are

discontinued, full strength is restored, although this may take days.

In general, the lowest dose of neuromuscular blocking agent should

be used to achieve the desired result, and when these agents are used

in the ICU, a peripheral nerve stimulator should be used to monitor

neuromuscular junction function.

■ MYOPATHY

Critically ill patients, especially those with sepsis, frequently develop

muscle weakness and wasting, often in the face of seemingly adequate

nutritional support. Critical illness myopathy is an overall term that

describes several different discrete muscle disorders that may occur in

critically ill patients. The assumption has been that a catabolic myopathy may develop as a result of multiple factors, including elevated cortisol and catecholamine release and other circulating factors induced by

the SIRS. In this syndrome, known as cachectic myopathy, serum creatine kinase levels and electromyography (EMG) are normal. Muscle

biopsy shows type II fiber atrophy. Panfascicular muscle fiber necrosis

may also occur in the setting of profound sepsis. This less common

acute necrotizing intensive care myopathy is characterized clinically by

weakness progressing to a profound level over just a few days. There

may be associated elevations in serum creatine kinase and urine myoglobin. Both EMG and muscle biopsy may be normal initially but eventually show abnormal spontaneous activity and panfascicular necrosis

with an accompanying inflammatory reaction. Acute rhabdomyolysis

can occur from alcohol ingestion or from compartment syndromes.

A thick-filament myopathy may occur in the setting of glucocorticoid and nd-NMBA use. The most frequent scenario in which this is

encountered is the asthmatic patient who requires high-dose glucocorticoids and nd-NMBA to facilitate mechanical ventilation. This muscle

disorder is not due to prolonged action of nd-NMBAs at the neuromuscular junction but, rather, is an actual myopathy with muscle damage; it

has occasionally been described with high-dose glucocorticoid use or

sepsis alone. Clinically this syndrome is most often recognized when

a patient fails to wean from mechanical ventilation despite resolution

of the primary pulmonary process. Pathologically, there may be loss of

2277 Nervous System Disorders in Critical Care CHAPTER 307

thick (myosin) filaments. Thick-filament critical illness myopathy has

a good prognosis. If patients survive their underlying critical illness,

the myopathy invariably improves and most patients return to normal.

However, because this syndrome is a result of true muscle damage,

not just prolonged blockade at the neuromuscular junction, this

process may take weeks or months, and tracheotomy with prolonged

ventilatory support may be necessary. Some patients do have residual

long-term weakness, with atrophy and fatigue limiting ambulation.

At present, it is unclear how to prevent this myopathic complication,

except by avoiding use of nd-NMBAs, a strategy not always possible.

Monitoring with a peripheral nerve stimulator can help to avoid the

overuse of these agents. However, this is more likely to prevent the

complication of prolonged neuromuscular junction blockade than it is

to prevent this myopathy.

■ FURTHER READING

Callaway CW et al: Part 4: Advanced life support: 2015 international

consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Circulation

132:S84, 2015.

Cook AM et al: Guidelines for the acute treatment of cerebral edema in

neurocritical care patients. Neurocrit Care 32:647, 2020.

Dhar R: Neurologic complications of transplantation. Handb Clin

Neurol 141:545, 2017.

Donnelly J et al: Regulation of the cerebral circulation: Bedside

assessment and clinical implications. Crit Care 20:129, 2016.

Posner JB et al: Plum and Posner’s Diagnosis and Treatment of Stupor

and Coma, 5th ed. New York, Oxford University Press, 2019.

Quillinan N at al: Neuropathophysiology of brain injury. Anesthesiol

Clin 34:453, 2016.

Rubin D et al: Clinical predictors of neurotoxicity after chimeric antigen receptor T-cell therapy. JAMA Neurol 77:1, 2020.

Sandroni C et al: Prognostication in comatose survivors of cardiac

arrest: An advisory statement from the European Resuscitation

Council and the European Society of Intensive Care Medicine. Intensive Care Med 40:1816, 2014.

Toledano M, Fugate JE: Posterior reversible encephalopathy in the

intensive care unit. Handb Clin Neurol 141:467, 2017.

Vanhorebeek I et al: ICU-acquired weakness. Intensive Care Med

46:637, 2020.

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Disorders of the Kidney and Urinary Tract PART 9

Approach to the Patient

with Renal Disease or

Urinary Tract Disease

Julian L. Seifter

308

The upper urinary tract consists of the kidneys, their vasculature, and

the renal parenchyma and its collecting system. The lower urinary

tract is composed of the peristaltic ureters from each kidney, the bladder which receives and stores urine from each ureter, and the urethra

which, upon bladder contraction, excretes the final urine. The excretory system as a whole begins with a plasma ultrafiltrate from renal

cortical glomeruli, modified by the renal tubules of the nephron, and

ends with the excretion of urinary water and solutes.

Disease can occur at any level of these functional structures with

either no symptoms or signs (such as an incidental renal mass picked

up on ultrasound); with nonspecific findings (such as fatigue); with

signs highly specific for a syndrome of dysfunction referable to a structure, but not diagnostic of a particular disease (such as proteinuria);

or with a finding highly characteristic of a specific diagnosis (such as

polycystic kidney disease). Disorders of the kidney presenting without

symptoms (such as invisible microhematuria or a stone) are often discovered by laboratory testing or imaging.

It is important to perform renal testing in patients with systemic

disease (for example, routine screening for albuminuria in diabetes

mellitus [DM]). Likewise, one should look at renal function when a

patient’s history includes known risk for renal or urinary tract complications (for example lithium for psychiatric treatment, occupational

use of lead, or, in the case of bladder cancer, exposure to aniline dyes).

This chapter will address an approach to patients with and without

known history of kidney disease, as well as those who have one of a

wide variety of systemic illnesses that involve the kidney or the lower

urinary tract.

To begin with the evaluation of renal disorders, note that it is timeconsuming and wasteful to do random testing prematurely, which

would generate a very long list of potential diagnoses. A better approach

is to look at the evidence from the history, physical examination, and

basic laboratory studies to arrive at a logical basis for targeted tests that

would identify a particular disease process (Table 308-1). The findings

are influenced by the regions of the kidney that are involved and by

factors such as family history, toxic exposures, the patient’s birth weight

and age, and time course of the findings. As a rule, kidney diseases

that begin primarily with glomerular dysfunction have albuminuria as

the hallmark, whereas those kidney diseases that begin in the tubular

structures may present primarily with electrolyte disorders or disorders

of dilution and concentration of the urine. In both glomerular and

tubular disorders, upon progressing to chronic disease, the distinction

is more difficult because glomerular diseases eventually affect the

tubular interstitium and tubular diseases progress to glomerular dysfunction and scarring.

One example of the progression from a tubular disorder to chronic

kidney disease with late glomerular damage is the lysosomal storage

disease cystinosis, one of the childhood Fanconi’s syndromes. Within

the first year of life, the affected child may become easily dehydrated

from salt-wasting; feed and grow poorly; develop polyuria, hypotension,

and muscle weakness; and show the features of proximal tubular dysfunction. Electrolyte losses result in hypokalemic renal tubular acidosis

(RTA), renal glycosuria, phosphaturia causing growth delay from renal

rickets, and acidemia. The accumulation of lysosomal cystine leads to

destruction of the proximal tubule and adjacent interstitium, while glomerular filtration remains near normal and urine contains little albumin.

Even with treatment, progressive scarring of the capillaries within

the interstitial space eventually, over a decade or more, leads to albuminuria and progressive decrease in GFR. Electrolytes like K+ and

HPO4

= are retained at this stage and metabolic acidosis results from

failure of the kidney to produce NH4

+ rather than losses of HCO3

-

.

Hypertension and edema from salt and water retention replace the

low blood pressure associated with the loss of fluid at the earlier stage

of tubular dysfunction. Anemia results from loss of erythropoietin

production in chronic kidney disease. The symptoms of weakness and

fatigue are nonspecific in that they might correlate with anemia, hypoor hyperkalemia, hypophosphatemia, acidosis, l-carnitine deficiency

from proximal tubule reabsorptive failure in Fanconi’s syndrome, or

azotemia. Hepatomegaly on a newborn examination, typical of but not

specific to cystinosis, might raise suspicion of other inborn errors of

metabolism such as glycogen storage diseases. However, the finding of

photosensitivity related to highly refractile cystine crystals deposited in

the cornea is very specific for cystinosis.

In the following discussion, the focus is on symptoms and signs

that constitute the major syndromes seen in the patient with kidney or

lower urinary tract disease. These syndromes are the foundation for the

diagnosis of particular diseases.

TABLE 308-1 Acute Kidney Injury

FEATURES PRERENAL RENAL POSTRENAL

CONTEXT Heart failure, hepatic failure,

burns, shock, post-op, dehydration,

renovascular disease, vascular drugs

ATN, bilateral cortical necrosis, AIN, crush

injuries, myoglobulinuria, hemoglobinuria,

ischemia, sepsis, recent contrast drugs

Bladder outlet obstruction, obstruction of

solitary kidney, abdominal mass, bilateral

stones, drugs

URINE OUTPUT Oliguria (usually <500 mL/day)

Anuria

Oliguria

Normal

Polyuria

Anuria

Polyuria

Both

CLINICAL HISTORY AND

EXAM

Trauma, shock, hypotension, burns, GI,

sweat, or renal losses

Rhadomyolysis, hemolysis, thrombotic

microangiopathy, AIN, atheroemboli

Extrinsic ureteral obstruction, retroperitoneal

disease, bladder outlet or urethral obstruction

by prostate or cervical cancer

URINALYSIS Concentrated acid urine, hyaline casts,

crystalluria

“Muddy brown” granular casts, hematuria,

dysmorphic RBCs, RBC casts in GN, WBC

casts in AIN, eosinophils in atheroemboli

Intrarenal obstruction by uric acid or calcium

phosphate in tumor lysis syndrome, blood clots

in lower urinary tract bleeding, CaOx after

ethylene glycol ingestion

URINE CHEMISTRY Low FENa ≤1%, U/P Cr ≥40, UNa ≤10,

U/P Osm ≥1

FENa 1–3%, U/P Cr ≤40, UOsm ~Isomotic Early looks like prerenal, late looks like renal

LABORATORY STUDIES High BUN/Cr ratio, usually

hypercatabolic with increased uric acid;

may have hyper- or hyponatremia

May have eosinophilia in allergic AIN, high

phosphate, low Ca, high PTH, metabolic

acidosis

Hydronephrosis on ultrasound, extrinsic or

instrinsic diseases on CT scan, tumors on MRI

2280 PART 9 Disorders of the Kidney and Urinary Tract

NEPHRITIC SYNDROMES

Nephritis literally means an inflammatory condition of the kidney.

Nephritic inflammation may occur in association with infection, allergic response to medications, systemic autoimmune disorders, or toxic

exposures. The kidneys may be one of many organs, or the only organ,

involved in the inflammatory disorder. Inflammation with enlargement of the kidneys is often associated with point tenderness over the

flank and sometimes exquisite costovertebral angle tenderness, requiring gentle palpation for diagnosis.

The nephritic syndromes may be further subdivided depending on

the inflamed structures within the kidney, including vascular, glomerular, and tubulointerstitial; and also, on the time course of progression

of the inflammatory process, which may be acute, subacute, or chronic.

■ GLOMERULONEPHRITIS

Glomerulonephritis (GN) is associated with hypertension, volume

expansion, and an abnormal urinalysis. In most cases, the volume

expansion manifests as edema and hypertension; in the child, ascites may

develop; and in the elderly, restlessness and anxiety may be the first signs

of incipient acute pulmonary edema. There may be orthopnea at night or

dyspnea on exertion, with or without significant peripheral edema. Acute

GN is usually associated with low urine output (oliguria or at times complete anuria), low urine sodium content, and concentrated urine, resulting in the retention of salt and water. It is an absolute necessity to observe

the urine, including a spun urinary sediment, to diagnose active GN.

The disease presentation may be acute or subacute (postinfectious

GN and rapidly progressive GN), occurring over days or weeks; or it

may be chronic, occurring over many months to years. The pathologic correlate of these presentations—the relative amount of acute

inflammatory, proliferative, or necrotizing lesions in renal tissue versus chronic sclerotic and atrophic findings on renal biopsy—reflects

the acuity versus chronicity of disease. Therefore, in these progressive

destructive conditions, early diagnosis is critical and treatment for

acute reversible disease should be instituted as quickly as possible.

The evaluation of the findings on history, physical examination,

and urinalysis in narrowing diagnostic possibilities for a specific etiology of the glomerular syndromes is demonstrated in Fig. 308-1. The

nephritic urinalysis shows hematuria, proteinuria, cells or clumps of

cells, and cellular casts in the spun urinary sediment. The cells in the

urine are usually a mixture of red blood cells and inflammatory cells,

including polymorphonuclear (PMN) leukocytes. Microscopic hematuria is invisible to the naked eye, as opposed to macroscopic hematuria, identifiable as cola or “tea-colored” urine, caused by hemoglobin

entering an acid urine. The red cells enter the renal tubules through

breaks in the basement membrane of glomeruli. The process of moving

across the membrane causes erythrocytes to become misshapen or dysmorphic. It is unusual in these nephritic syndromes to see blood clots

or gross hematuria, a term used for overtly blood-red urine that characterizes other syndromes or lower urinary tract bleeding. However, in

episodes of IgA nephropathy, glomerular hematuria is often “gross” as

RBCs traverse rents in the glomerular basement membrane (GBM).

Postinfectious Glomerulonephritis Postinfectious glomerulonephritis (PIGN) is the classic example of acute GN, a complementmediated immune complex response, to a bacterial antigen occurring 10

days to 3 weeks after a specific nephritogenic strain of group A streptococcal pharyngitis, or after skin infection such as impetigo. Because the sore

throat or skin infection may have already resolved, antibiotic treatment

may not be necessary at this stage of renal complication, but it is important for the clinician to inquire about these possible prior events. Subacute

bacterial endocarditis, if present by history, may also result in a circulating

immune complex disorder, even while the patient remains on antibiotic

treatment. These glomerulonephritic and other immune complex conditions are recognized by low-C3 complement levels in the blood. However,

the postinfectious cases should be distinguished from cases of infectionassociated glomerulonephritis that occur during an ongoing infection,

such as a staphylococcal (often MRSA) abscess or empyema, which are

treated with antibiotics and purulent drainage and are characteristically

associated with IgA and complement deposition in the glomeruli.

Postinfectious GN is to be distinguished from synpharyngitic hematuria, another glomerular syndrome that frequently produces gross

hematuria, a heavier excretion of red blood, which may appear to the

patient as a frightening hemorrhage. The patient may present with this

concern so it is important for the clinician to recognize that as little

as 10–20 mL of blood will turn a liter of urine red. Synpharyngitic

hematuria, usually with a viral pharyngitis, is most often related to IgA

nephropathy rather than postinfectious GN. Another feature that distinguishes IgA nephropathy from postinfectious GN is that the former usually demonstrates normal circulating C3 complement as opposed to low

complement in PIGN. IgA nephropathy can cause chronic microhematuria or bouts of gross hematuria or can occur in association with other

immunologic conditions including celiac disease, rheumatoid arthritis,

reactive arthritis, and ankylosing spondylitis. IgA nephropathy and

staphylococcal-associated GN are more common in Asian populations.

RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS (RPGN) Rapidly

progressive glomerulonephritis (RPGN) is a syndrome arising from

a variety of causes (Fig. 308-1). Pathologically it is associated with a

proliferation of glomerular parietal epithelial cells and inflammatory

cells called cellular crescents surrounding the capillary that, over time,

becomes fibrotic and atrophic with global loss of the glomerular tuft.

RPGN

Low C3

Antiproteinase3

Granulomatous

Micropolyangiitis Antimyeloperoxidase

Renal-limited

Goodpasture,

with pulmonary

involvement

Postinfectious

SBE

Hepatitis B, C

SLE

Syphilis

Schistosomiasis

Tumor

Cryoglobulinemia

Anti-GBM

ANCA

FIGURE 308-1 Rapidly progressive glomerulonephritis. The syndrome of RPGN

is diagnosed clinically. The three major categories are the antineutrophilic

cytoplasmic antibodies (ANCA-positive vasculitities); antiglomerular basement

membrane antibody-positive (anti-GBM); and immune complex disorders with low

C3 complement. C3 is synthesized in the liver, bound to circulating infectious or

neoplastic antigens with their antibody complexes, and deposited in the glomerular

subendothelium is associated with non-renal manifestations. Syphilis is usually

accompanied by vasculitis, and cryoglobulins may be in setting of hepatitis C or

myeloma and often lowers C4 as well. SBE, subacute bacterial endocarditis; SLE,

systemic lupus erythematosus.

2281Approach to the Patient with Renal Disease or Urinary Tract Disease CHAPTER 308

When >50% of glomeruli are affected (diffuse), this highly destructive

process usually leads to glomerular sclerosis. Recognition of RPGN

and choice of appropriate therapy are extremely important because,

if left unchecked, the syndrome can lead to complete and irreversible

loss of kidney function, as well as fatal pulmonary hemorrhage when

associated with lung vasculitis.

In the case of RPGN, one sees the typical signs of the nephritic

syndrome, though other clues to diagnosis may be present in the

pulmonary-renal syndromes, where the patient may present with

hemoptysis, interstitial lung disease, epistaxis, or upper airway symptoms of sinusitis or nasal congestion. Blood testing helps narrow

the differential diagnosis. The antineutrophil cytoplasmic antibody

(ANCA) test, particularly those made up of antimyeloperoxidase

(pANCA) or antiproteinase-3 antibodies (cANCA), is diagnostic for

the pauci-immune disorders of systemic vasculitis. Granulomatous

vasculitis (formerly known as Wegener’s granulomatosis) and microscopic polyangiitis are conditions particularly associated with pulmonary and upper respiratory disease. By contrast, a positive test for

antiglomerular basement membrane (anti-GBM) antibodies would be

consistent with either renal-limited anti-GBM disease or, when associated with pulmonary hemorrhage, with Goodpasture disease. The

latter is more often seen in young males who smoke or have a history

of inhaling hydrocarbon solvents.

The immune complex diseases that manifest as RPGN have low

C3 levels secondary to high clearance of circulating complement with

immune complex deposits in the glomerular subendothelial space.

Certain of these disorders, such as systemic lupus erythematosus (SLE)

and cryoglobulinemia, can present with pulmonary hemorrhage.

Patients with cryoglobulinemia often have low C4 complement and a

high rheumatoid factor, and the syndrome may be caused by paraproteinemias or hepatitis C. Another cause of crescentic RPGN but with

normal C3 complement is a form of IgA vasculitis (Henoch-Schonlein

purpura), a syndrome of skin vasculitis characterized by palpable purpura, gastrointestinal bleeding, and arthralgias, and in the vasculitic

form, pulmonary hemorrhage. The C3 complement (an acute phase

reactant) is detected in the kidney biopsy but not associated with low

serum levels. The diagnostic tests and distinct diseases associated with

these immune complex disorders are shown in Fig. 308-1.

Tubulointerstitial Nephritis Tubulointerstitial nephritis (TIN)

comprises inflammatory disorders of the renal tubules and interstitium, which may be caused by infection, autoimmune disease, allergic

immunologic responses to certain drugs (Fig. 308-2) and have a time

course ranging from days to weeks and months.

ACUTE ALLERGIC AND IMMUNE INTERSTITIAL NEPHRITIS Acute

allergic or immune interstitial nephritis (AIN) usually occurs 1 day to

2 weeks following exposure to an offending drug and may be associated

with a rapid and potentially reversible loss of kidney function, which

may occur in the setting of a change in dose or the restarting of a previously used medication. Associated glomerular proteinuria sometimes

occurs with the use of nonsteroidal anti-inflammatory drugs (NSAIDs)

or ampicillin. Clinically, there may be fever, rash, and eosinophilia;

the last is typical for certain penicillins, fluoroquinolones, and some

biologic cancer drugs that act as checkpoint inhibitors (CPIs) but is

atypical for NSAIDs. Patients who recover from CPI-induced acute

kidney injury (AKI) may be restarted on the inhibitor.

The urinalysis usually shows pyuria and at times eosinophiluria,

but the most characteristic cell types are activated T lymphocytes and

plasma cells, along with some white blood cell casts. A cyto-centrifuged

specimen containing the sediment within a small tube mounted perpendicular to the slide, then stained with Giemsa, best demonstrates

these cell types.

The patient may experience symptoms of polyuria and tender kidneys, and signs of tubular dysfunction including nephrogenic diabetes

insipidus, hypo- or hyperkalemia and hyperchloremic metabolic acidosis. Common drugs that cause AIN include the proton pump inhibitors

(PPIs) and sulfa drugs, especially sulfamethoxazole, but also extending

to sulfa-containing diuretics such as acetazolamide, thiazides, and

furosemide, and less frequently, bumetanide. PPI’s may increase risk

for AIN in patients on check point inhibitors. Frequently, rifampin

and a few other drugs cause a noncaseating granulomatous interstitial nephritis; in caseating granulomas resulting from hematogenous

spread of mycobacterium tuberculosis, the first granulomas appear

connected to the glomeruli in the cortex where oxygen tension is at its

highest. Granulomatous TIN may occur in sarcoidosis.

Systemic infections including bacterial, viral, fungal, and parasitic

may induce tubulointerstitial nephritis, first described pathologically

in the preantibiotic era as Councilman’s nephritis in the course of

scarlet fever.

Autoimmune interstitial nephritis is seen in diseases such as lupus

nephritis, ANCA-positive vasculitis, and other rheumatic disorders

including Sjogren’s syndrome, which may present with dry eyes as part

of the sicca syndrome. In a patient with photophobia and red painful

eye, the clinician should look at renal function and the urinalysis for

evidence of tubulointerstitial nephritis uveitis (TINU) syndrome.

Noninflammatory Interstitial Diseases Noninflammatory

interstitial diseases are often caused by toxic exposures that damage

the tubular interstitial structures. For example, a cancer patient on

ifosfamide may develop Fanconi’s syndrome, indicating proximal

tubule damage. Heavy-metal exposures such as cadmium, lead, and

mercury from old dental fillings may lead to proximal tubule injury

and, again, Fanconi’s syndrome. A patient with hypomagnesemia and

acute kidney injury (AKI) may have had past exposure to platinumcontaining chemotherapeutic agents and a patient with nephrogenic

diabetes insipidus, unresponsive to antidiuretic hormone, may have

Acute

Tubulointerstitial

Nephritis

Allergic

Drug Toxicity

Immune

Infections

TB, Leptospirosis,

Mycoplasma,

Legionella, Lyme,

Councilmans

Sarcoid

SLE, Sjogrens

Lithium

NSAIDs

Allopurinol

Proton pump

inhibitors

Oncologic agents:

checkpoint

inhibitors

Antibiotics:

cephalosporin,

rifampin, penicillins,

sulfa, quinolones

FIGURE 308-2 Acute tubulointerstitial nephritis. Diseases resulting from injury to

the tubular and interstitial components of the renal cortex and medulla.

2282 PART 9 Disorders of the Kidney and Urinary Tract

had treatment with lithium, analgesics, or chemotherapy. Hypokalemia

and interstitial disease are consistent with a past history of exposure to

aminoglycosides or amphotericin-B. The patient with the former may

complain of hearing loss and the patient with the latter may present

with hypokalemia and RTA.

Chronic interstitial diseases should be suspected in cases of paraproteinemia (light-chain nephropathy or amyloidosis) and in patients who

ingest herbal remedies containing aristolochic acid, as occurs commonly

in China and has been determined to be the cause of Balkan nephropathy. Perhaps the most common cause of chronic interstitial nephritis

is prolonged analgesic use to treat chronic pain (not only NSAIDs but

acetaminophen or combinations of phenacetin, aspirin, and caffeine) as

part of the analgesic syndrome. The clinician should ask about a prior

history of pain and also gastrointestinal symptoms that may precede the

kidney disease; the analgesic drugs often go unreported by the patient.

It is important to recognize this syndrome because, if the drugs are not

discontinued, a later development may be urothelial cancers of the distal

ureter and urinary bladder. Lithium after prolonged use can also cause

chronic interstitial nephritis along with nephrogenic diabetes insipidus

and slowly progressive kidney failure.

Patients who have hypercalcemia or hyperoxaluria may develop

nephrocalcinosis, a form of interstitial nephritis characterized by calcifications within the renal parenchyma, often at the cortical medullary

boundary. When nephrocalcinosis and nephrolithiasis are concurrent,

the most common etiologies include hypercalcemic disorders, particularly primary hyperparathyroidism, and congenital medullary sponge

disease (tubular ectasia), as well as hereditary distal RTA. In patients

with DM, chronic analgesic use, or sickle-cell diseases, the phenomenon of papillary necrosis is associated with chronic interstitial damage

characterized by nephrogenic diabetes insipidus. For example, phenacetin toxicity is a result of the drug’s concentrating in the medulla due

to the normal urinary concentrating mechanism; ironically, the first

function lost because of medullary toxicity is the ability to concentrate

the urine. In the ensuing papillary necrosis, the patient may observe

solids in the urine, which are sloughed tissue from the ischemic

medulla. When a patient with inflammatory bowel disease or one who

has had gastric bypass procedures such as the Roux-en-Y develops

kidney injury, with or without calcium oxalate kidney stones, a 24-h

urine oxalate measurement must be determined to diagnose intestinal

hyperoxaluria, which otherwise may lead to nephrocalcinosis. Chronic

bacterial pyelonephritis is not a common cause of chronic renal failure

because it rarely affects both kidneys. Acute pyelonephritis in a solitary

kidney or transplanted kidney may cause AKI.

■ PROTEINURIC STATES AND NEPHROTIC

SYNDROME

Proteinuric States Some patients notice generalized edema and

foamy urine, manifestations of proteinuria. Proteinuria is not synonymous with nephrotic syndrome (NS). In DM the urinary loss of

microalbuminuria (MALB) defines glomerular proteinuria, which

typically occurs after years of small-vessel disease (explaining the

likelihood of coincident small-vessel retinopathy) and predicts future

development of progressive renal failure and NS. The rate of renal

progression is greater with hypertension, obesity, and poor glucose

control. Further risks are nephrectomy, hepatitis C, and, as in focal

segmental glomerular sclerosis (FSGS), in patients of African ancestry

is likely due to the prevalence of the APOL1 gene mutations. Because

treatment of patients with MALB is indicated, the clinician caring

for diabetic patients should screen regularly for the presence of small

amounts of albumin in the urine, which can be detected as microalbuminuria (30–300 mg/day of albumin excretion) by radioimmunoassay.

Subnephrotic albuminuria is characteristic of focal diseases of the

kidney with <50% of glomeruli involved, whereas NS is likely diffuse,

involving most glomeruli. Lower levels of albuminuria are characteristic of glomerulonephritis, as discussed above.

Microalbuminuria is beneath detection by urinary dipstick protein analysis. Any detectable albuminuria on dipstick is called overt

proteinuria and when detected at the highest level on the strip is

consistent with nephrotic proteinuria. The dipstick measurement picks

up only the most acidic proteins like albumin but not proteins with a

higher isoelectric point, most notably kappa and lambda light chains

found in multiple myeloma. Additionally, the filtration of light chains

may cause glomerular damage and albuminuria (kappa light-chain

nephropathy or lambda AL amyloid) but does not require an abnormal

glomerulus because their charge and molecular weight allow them to

freely cross the glomerular barrier. Such filtration is considered overflow proteinuria.

A laboratory measurement of albumin or total protein should be

normalized to urine creatinine concentration as a ratio in order to discount the effects of urinary dilution or concentration. It is also important to note that the ratio of total protein concentration to creatinine

concentration is not specific for albumin excretion and may indicate

the presence of light chains. The detection of light chains requires a

urine protein electrophoresis.

Another type of proteinuria known as tubular proteinuria, which is

mostly β-2 microglobulin, is secreted by proximal tubular cells and is

common in interstitial nephritis.

Nephrotic Syndrome Nephrotic syndrome (NS) has three defining features: edema, hypoalbuminemia (<3.5 g/dL), and proteinuria

>3.5 g/day. The syndrome is often associated with lipid abnormalities

such as a high LDL, low HDL, and lipiduria. The urine may contain

large tubular epithelial cells that are engulfed with the lipid in a recognizable shape under polarized light. These oval fat bodies may also

contain cholesterol monohydrate crystals, which appear as Maltese

crosses. Under low light, the refractile lipid may be seen as fatty casts.

Clinically, patients present with generalized edema and, in contrast

to heart failure with orthopnea, facial, eyelid and periorbital swelling

is observed in NS. Penile and scrotal edema can be severe enough to

obstruct urethral urine flow in men. In some cases, edema may form

large bullae that may rupture, predisposing to ulceration and cellulitis.

The skin becomes smooth and may appear to “weep.” Patients may

have hoarseness caused by vocal cord edema. On occasion, nephrotic

range proteinuria is not associated with edema, for example in the case

of human immunodeficiency virus-associated nephropathy (HIVAN),

which is more common in blacks with HIV. In these cases, rapid loss of

renal function may occur due to implosion of the glomerular capillary

by proliferation of visceral epithelial cells that crush the glomerular

loops, decreasing capillary flow and filtering surface area (collapsing

glomerulopathy). This glomerulopathy is a severe, treatment-resistant

form of FSGS. Other secondary forms of FSGS, more often not associated with NS, include remnant kidney after partial surgical removal,

adaptive injury, chronic hypoxemia, sickle cell diseases, recurrent

vasculitis with healing of some glomeruli, obesity, and congenital

urogenital anomalies. Very heavy proteinuria is often noted in this

syndrome. Secondary forms of FSGS are shown in Fig. 308-3. Other

secondary forms of FSGS, more often not associated with NS, include

remnant kidney after partial surgical removal, adaptive injury, chronic

hypoxemia from chronic lung or congenital heart disease, sickle cell

diseases, recurrent vasculitis with healing of some glomeruli, obesity,

and congenital urogenital anomalies.

NS is a hypercatabolic state with negative nitrogen balance due

to proximal tubule absorption and lysosomal catabolism exceeding

hepatic albumin synthesis. A characteristic finding of rapid-onset

hypoalbuminemia in NS is horizontal linear white lines in the nail bed,

known as Muehrcke’s lines. When NS in the adult occurs abruptly, with

severe elevation of cholesterol, one must consider glomerular epithelial

injury (podocytopathy), which may be idiopathic minimal change

disease (MCD), a name historically based on the appearance of renal

tissue on light microscopy and often preceded by an upper respiratory

infection, allergies, or immunization. Secondary causes of MCD are

Hodgkin’s lymphoma or other lymphoproliferative disorders. MCD can

occur at any age and in the adult may present with AKI as well, primarily because of the underlying vascular disease and hypoalbuminemia.

Age is important in the onset of NS, in that young children <6 years

of age frequently have MCD. Several gene mutations encoding for proteins of the podocyte, such as nephrin (NPHS1) and podocin (NPHS2)