Neurologic Aspects of Kidney Disease - Brenner and Rector's The Kidney, 8th ed

Brenner and Rector's The Kidney, 8th ed.

CHAPTER 51. Neurologic Aspects of Kidney Disease

Allen I. Arieff

		Acute Kidney Injury, 1758
		Chronic Renal Failure, 1758
		Central Nervous System Manifestations of Renal Failure, 1758
		Uremic Encephalopathy, 1758
		Radiologic and Pathologic Findings in Uremic Brain, 1763
		Nervous System Manifestations of End-Stage Renal Disease, 1763
		Chronic Dialysis-Dependent Encephalopathy, 1763
		Apoptosis, 1764
		Oxidative Stress, 1764
		Inflammation, 1765
		Homocysteine, 1765
		Uremic Neurotoxins in Patients with Chronic Renal Failure, 1765
		Central Nervous System, 1765
		Peripheral Nervous System, 1766
		Neurologic Complications of End-Stage Renal Disease and Its Therapy, 1767
		Dialysis Dysequilibrium Syndrome, 1767
		Dialysis Dementia, 1768
		Other Central Nervous System Complications of Dialysis, 1771
		Subdural Hematoma, 1771
		Technical Dialysis Errors, 1772
		Stroke in Patients with Renal Insufficiency Treated with Hemodialysis, 1772
		Mechanisms of Cell Damage with Stroke, 1772
		Demographics of Stroke in Patients with Renal Insufficiency, 1772
		Chronic Inflammation and Cerebrovascular Disease, 1773
		Therapy of Stroke, 1773
		Chronic Inflammation and Cardiovascular Disease, 1774
		Prevention of Stroke, 1774
		Management of Stroke, 1775
		Sexual Dysfunction in Uremia, 1775
		Pathogenesis of Uremic Sexual Dysfunction, 1775
		Therapy of Sexual Dysfunction in Uremia, 1775
		Uremic Neuropathy, 1776
		Clinical Manifestations, 1776
		Peripheral Nerves, 1776
		Metabolic Neuropathy, 1776
		Uremic Toxins and Nerve Conduction, 1777
		Parathyroid Hormone, 1777

Although technical advancements in dialysis therapy, improved immunosuppres-sion with renal transplantation, and overall improvements in medical management have resulted in improvement of both the duration and quality of life in patients with end-stage renal disease (ESRD), this progress has introduced major drawbacks. The disorders introduced by extended longevity among patients with ESRD include amyloid-associated arthropathy^[1] and myocardiopathy,^[2] increased frequency of leg amputation among diabetic subjects treated with hemodialysis,^[3] ever more severe coronary artery disease,^[4] and left ventricular hypertrophy, largely as a consequence of uremic anemia.^{[5] [6]} Recent evidence suggests a common linkage of oxidative stress and carbonyl stress with increased cardiovascular morbidity and mortality.^{[7] [8] [9]} Patients with ESRD continue to manifest an increasing variety of neurologic disorders. Those with chronic renal failure who have not yet received dialysis therapy may develop a symptom complex progressing from mild sensorial clouding tremor to delirium and coma.^[10] Even after the institution of otherwise adequate maintenance dialysis therapy, patients may continue to manifest more subtle nervous system dysfunction such as impaired mentation, generalized weakness, sexual disfunction, and peripheral neuropathy. The central nervous system (CNS) disorders of untreated renal failure have traditionally been referred to as uremic encephalopathy. In this chapter, I have previously introduced a new concept, that of a syndrome of central nervous system disorders persisting despite otherwise adequate hemodialysis.^[11] This new disorder has been called Dialysis-Dependent Encephalopathy ( Table 51-1 ). The maintenance of life by treatment of patients with end-stage renal disease with dialysis has itself been associated with the emergence of at least four previously well-described disorders of the central nervous system: (1) dialysis dysequilibrium syndrome, (2) dialysis dementia, (3) stroke, and (4) sexual dysfunction.^{[12] [13] [14] [15]} The dialysis disequilibrium syndrome is a consequence of the initiation of dialysis therapy in a minority of patients. Dialysis dementia is a progressive, generally fatal encephalopathy that can affect patients on chronic hemodialysis as well as children with chronic renal failure who have not been treated with dialysis.

Cardiovascular disorders are the major cause of death in hemodialysis patients, accounting for in excess of 50% of deaths.^{[16] [17]} These include myocardial infarction, cardiomyopathy, ischemic heart disease, and stroke.^[18] The factors associated with uremia that lead to an increased incidence and mortality from stroke are not well known, but are beginning to be understood, as they are similar to those factors that lead to myocardial infarction.^{[16] [18] [19]}

In addition to these manifestations of neurologic dysfunction that are specifically related to renal insufficiency, dialysis, or both, a number of other neurologic dis-orders occur with increased frequency in patients who have end-stage renal disease and are being treated with chronic hemodialysis. Subdural hematoma, acute stroke, certain electrolyte disorders (hyponatremia, hypernatremia, hyperkalemia, phosphate depletion, hypercalcemia), vitamin deficiencies, Wernicke encephalopathy, drug intoxication, hypertensive encephalopathy, and acute trace element intoxication must be considered in patients with chronic renal failure who manifest an altered mental state. In the recent past renal transplantation was associated with a variety of nervous system infections and neoplasms, such as reticulum cell sarcoma and lymphoma, which were probably a direct result of immunosuppressive therapy then in use (azathioprine, prednisone). This appears to be altered with the current widespread use of other immunosuppressive regimens (mycophenolate mofetil, cyclosporin, tacrolimus, rapamycin, polyclonal antisera) for renal transplantation.^{[20] [21]}

Patients with renal failure are also at risk to develop the same varieties of organic brain disease and metabolic encephalopathy that can affect the general population. Therefore, when a patient with end-stage kidney disease presents with altered mental status, a thorough and complete evaluation is necessary.

TABLE 51-1 -- Chronic Dialysis-Dependent Encephalopathy

Neuroimaging of uremic brain—generally unremarkable

Pathology of uremic brain—generally nonspecific

Pathophysiologic mechanisms

Apoptosis

Calcium ion

Free radicals

Glutamate

Hypoxia

Oxidative stress

Advanced glycation end products

Metabolism of lipids

Metabolism of carbohydrates

Inhibited by nitric oxide donors

Inflammation

Elevated C-reactive protein

Elevated homocysteine

Occult infection

Occult inflammatory nidus

ACUTE KIDNEY INJURY

The clinical manifestations of acute kidney injury have been studied in several large patient series.^{[22] [23] [24]} Abnormalities of mental status have been noted as early and sensitive indices of a neurologic disorder, which progressed rapidly into disorientation and confusion.^[25] Fixed attitudes, torpor, and other signs of toxic psychosis were common. When uremia is untreated and allowed to progress, coma often supervenes. Cranial nerve signs such as nystagmus and mild facial asymmetries are common, though usually transient. There can be visual field defects and papilledema of the optic fundi. About half the patients have dysarthria, and many have diffuse weakness and fasciculations. Marked variation of deep tendon reflexes is noted in most patients, often in an asymmetrical pattern. Progression of hyperreflexia, with sustained clonus at the patella or ankle, is common.^[26] In contrast to patients with chronic renal failure, those with acute renal failure do not generally have long histories of diabetes mellitus and do not tend to have the extensive cardiovascular damage, which is found in so many patients with chronic ESRD.

CHRONIC RENAL FAILURE

The incidence of new cases of ESRD in the United States (2003) is 338 new cases per million population.^[27] There is a gender difference, with a 47% greater incidence among males (413 per million) versus females (280 per million). The prevalence of ESRD in the United States (2003) is about 1500 cases per million.^[27] There are currently 452,057 individuals in the Unisted States with ESRD, of which 324,836 were treated with dialysis, 298,101 with hemodialysis.^[27] The overall annual Medicare cost per patient to deliver 1 year of maintenance hemodialysis is about $68,000.^[28] Among patients with ESRD treated with chronic hemodialysis, the mortality in the United States is 21% per year.^[29] This figure is substantially higher than that of Japan and most European countries.^[30] Although it is unlikely that any one factor is responsible for the higher mortality in the United States versus Europe and Japan, two important factors might be dialyzer reuse and a higher percent of ESRD secondary to diabetes mellitus in the United States.^[31] In addition, there may be racial differences in mortality among African American, Asian, and White patients.^[30] Reuse of dialyzers in the United States is a common cost-containment procedure.^[32] The opportunities for contamination, increased cytokine production, and infection associated with dialyzer reuse are substantial.^[33]However, evaluation of 1- to 2-year follow-up data in 12,791 patients treated in 1394 dialysis facilities from 1994 to 1995 was carried out. These data showed that the relative risk (RR) for morality did not differ for patients treated with reused dialyzers versus single-use systems.^[34] Thus, the question remains open.

In the United States, the most frequent causes of ESRD are diabetes, hypertension, glomerulonephritis, and polycystic kidney disease.^[35] However, in 2006, diabetes has overtaken all other causes of end-stage renal disease (ESRD) in the United States and other Western countries.^{[31] [36] [37]} This trend has resulted in more kidney transplants in older diabetic patients.^[38]

The neurological manifestations reported in patients with chronic renal failure (CRF) are numerous.^[25] These have recently expanded due to the increased number of diabetic patients with ESRD.^[31] Diabetes adds its own list of neurological manifestations,^[39] which will then be combined with those due to CRF.^[39]

CENTRAL NERVOUS SYSTEM MANIFESTATIONS OF RENAL FAILURE

Uremic Encephalopathy

Uremic encephalopathy is a metabolic encephalopathy that has much in common with other types, such as diabetic ketoacidosis, hepatic failure, hypoxia, carbon dioxide narcosis, and acute ethanol intoxication.^{[40] [41]} The symptoms of uremic encephalopathy are shown in Table 51-2 . Uremic encephalopathy is an acute or subacute organic brain syndrome that regularly occurs in patients with acute or chronic renal failure when glomerular filtration rate declines below 10% of normal. As with other organic brain syndromes, these patients display variable disorders of consciousness, psychomotor behavior, thinking, memory, speech, perception, and emotion.^{[10] [22] [42]} The term uremic encephalopathy is used to describe the early appearance and dialysis responsiveness of the nonspecific neurologic symptoms of uremia. Other systemic abnormalities observed in patients with chronic renal failure are separable from uremic encephalopathy on the grounds that they tend to appear late in the progressive clinical course, infrequently produce symptoms, are detected in tissues and organs rather than as integrated whole organism phenomena, and respond sluggishly and irregularly to dialysis procedures. The symptoms may include sluggishness and easy fatigue; daytime drowsiness and insomnia with a tendency toward sleep-inversion; itching; inability to focus or sustain attention or to perform mental (cognitive) tasks and manipulation; inability to manage ideas and abstractions; slurring of speech; anorexia, nausea, and vomiting (probably of central origin); restlessness; imprecise memory; diminished sexual interest and performance; volatile emotionality and withdrawal; myoclonus and “restless legs”; “burning feet”; asterixis; hiccoughs; paranoid thought content; disorientation and confusion with bizarre behavior; hallucinosis, muttering and mumbling; meningeal signs, nystagmus; vertigo and ataxia; transient pareses and aphasic episodes; coma and convulsions.

TABLE 51-2 -- Signs and Symptoms of Uremic Encephalopathy

Early uremia

Anorexia

Malaise

Insomnia

Diminished attention span

Decreased libido

Moderate uremia

Emesis

Decreased activity

Easy fatigability

Decreased cognition

Impotence

Advanced uremia

Severe weakness and fatigue

Pruritus

Disorientation

Confusion

Asterixis

Stupor, seizures, coma (all rare after 1990)

Certain salient characteristics of the symptoms of uremic encephalopathy are especially noteworthy: they are due to dysfunction of the nervous system and are manifested as cognitive, neuromuscular, somatosensory, and autonomic impairments; their severity and overall rates of progression vary directly with the rate at which renal function develops. Uremic symptoms are generally more severe and progress more rapidly in patients with acute renal failure than in those with chronic renal failure. In more slowly progressive chronic renal failure the number and severity of symptoms also typically vary cyclically, with intervals of acceptable well-being in an otherwise inexorable downhill course toward increasing disability. The symptoms are readily ameliorated by dialysis procedures and suppressed by maintenance dialysis regimens. They are also usually relieved entirely following restoration of renal function (e.g., after successful renal transplantation). Thus the encephalopathy of renal failure is important to recognize precisely because it is promptly and decisively treatable by clinical methods that are generally available. The causes of uremic encephalopathy are doubtless multiple and complex. Brain oxygen utilization is diminished in patients with end-stage renal disease.^[43] Although most such individuals had anemia, correction of the anemia only partially improved the impaired brain oxygen utilization.^[43] However, because the widespread introduction of recombinant human erythropoietin (EPO) as a therapeutic agent in patients with end-stage renal disease (ESRD) treated with hemodialysis,^[44] it is now clear that brain function and quality of life are improved by correction of the anemia with EPO.^{[45] [46] [47] [48]} Predialysis patients (creatinine clearance below 50 ml/min) often have left ventricular hypertrophy, which can be corrected by administration of EPO.^[49] Cardiac effects of EPO are not limited to those secondary to correction of anemia, as EPO also leads to ventricular remodeling and inhibition of apoptosis.^{[50] [51]}

Diagnosis of Uremic Encephalopathy

The diagnosis of uremic encephalopathy in most patients is suspected if there is a constellation of clinical signs and symptoms that indicate that there is renal or urologic disease or injury. However, the presenting symptoms of uremia as mentioned earlier are similar to many other encephalopathic states. Thus there is a risk of misdiagnosis and mistreatment. The differential diagnosis is even more complex because patients with renal failure are subjected to other intercurrent illnesses that may also induce other encephalopathic effects. Moreover, if a drug or its metabolites with potential central nervous system toxicity is excreted or significantly metabolized by the kidney, the ensuing encephalopathic symptoms may not be entirely attributable to “uremia” but to the drug that has reached toxic levels at ordinary dose rates. When levels of azotemia are discovered that are sometimes associated with uremic encephalopathy in the absence of associated illness, differentiation of the effects of drug versus renal failure may be very difficult. One or more dialysis treatments may both restore more normal body fluid composition and also reduce drug levels, so that the question remains moot while the patient recovers. Despite the possibilities that such multiple causes of encephalopathy might occur simultaneously, uremic encephalopathy may be successfully differentiated in most instances by means of the usual clinical and laboratory methods.

Role of Parathyroid Hormone

Although there are many factors that contribute to uremic encephalopathy, most investigators have shown no correlation between encephalopathy and any of the commonly measured indicators of renal failure. In recent years, there has been considerable discussion of the possible role of parathyroid hormone as a uremic toxin. There is a substantial amount of evidence to suggest that parathyroid hormone may exert adverse effects on the central nervous system.^{[24] [52] [53] [54]}

Uremic Encephalopathy in Patients with Hepatic Insufficiency

In patients who have advanced liver disease with hepatic insufficiency, it is often difficult to differentiate whether the cause of encephalopathy is due to either hepatic or renal causes. Under normal conditions, protein and amino acids in the gastrointestinal tract are metabolized by colonic bacteria and mucosal enzymes to form ammonia.^[59] Ammonia then enters the liver through the portal circulation where it participates in the urea cycle to form urea. Over 90% of the urea produced is excreted in the urine and the remainder enters the colon via hepatoportal recirculation. However, in patients with renal failure, the major route for elimination of urea is not available; thus, the increase in blood urea. The amount of urea that enters the colon is increased because of the elevated plasma urea. Urea is then acted on by colonic bacteria and mucosal enzymes, leading to increased ammonia production, which may increase plasma ammonia levels. Plasma ammonia levels have been shown to correlate well with the severity of hepatic encephalopathy.^[60]

If the patient with kidney failure also has some other form of hepatic insufficiency, such as hepatitis, this additional ammonia load may present a stress that cannot be adequately handled by the diseased liver. The result may be increased blood and central nervous system ammonia levels with development of encephalopathy.^[59] Thus, patients with liver damage and end-stage kidney disease are at particular risk for developing encephalopathy because both conditions act synergistically to increase blood ammonia. Ammonia can be readily removed from the blood by hemodialysis. The increased incidence of hepatitis C in the United States has led to a major increase of dialysis patients with liver damage^[61] and elevated ammonia levels. It should also be noted that plasma urea and serum creatinine do not always adequately reflect renal function in patients with severe liver disease. Additionally, many patients who have liver disease, ascites, and normal plasma urea and creatinine may in fact have severe renal functional impairment.^{[62] [63] [64]} Among such individuals, differentiation of hepatic from uremic encephalopathy on clinical grounds is more difficult.

Electroencephalogram in Patients with Renal Failure

The electroencephalograms (EEG) were in the recent past a means for evaluating the adequacy of dialysis. Although generally useful in this regard, interpretation of the EEG in patients with chronic renal failure required skills not possessed by any but a small minority of Nephrologists.^[42] The EEG continued to be used for research purposes, but was only infrequently used for treatment of dialysis patients.^[65] The use of the EEG in treatment of dialysis patients has been superceded by the development of the Kidney Disease Outcomes Quality initiative in 2001, with frequent updates.^[66] Use of these guidelines does not require the skill to interpret the EEG. However, the EEG still contains much information about the status of the nervous system in various forms of renal insufficiency.

Electroencephalogram with Acute Kidney Injury

The EEG in patients with acute kidney injury^[24] has generally been grossly abnormal when the diagnosis of renal failure was first established. In most instances, the percentage of EEG power less than 5 Hz and less than 7 Hz, which are standard measurements of the percentage of EEG power devoted to abnormal (delta) slow wave activity, are over 20 times the normal value. The percentage of EEG frequencies above 9 Hz and below 5 Hz are not affected by dialysis for 6 to 8 weeks, but return to normal with recovery of renal function. Similar findings have been shown in experimental animals with renal failure.^[54] The EEG may worsen both during and for several hours after hemodialysis and up to 6 months after initiation of dialytic therapy.^{[67] [68]} In patients with acute renal failure, the EEG is abnormal within 48 hours of the onset of renal failure^[24] and is generally not affected by dialysis within the first 3 weeks ( Fig. 51-1 ). During this interval, patients with acute renal failure have been shown to have elevated levels of parathyroid hormone (PTH) in plasma.^{[24] [52]} Several months after return of renal function, plasma parathyroid hormone levels also return to normal. Although there are doubtlessly many factors that contribute to uremic encephalopathy, many investigators have shown no correlation between encephalopathy and any of the commonly measured indicators of renal failure (e.g., BUN, creatinine, bicarbonate, arterial pH, potassium).^{[24] [52] [65]} On this basis, parathyroid hormone has been postulated to be an important central nervous system “uremic toxin”.^{[52] [69]}



FIGURE 51-1 The molecular events initiated in brain tissue by acute cerebral ischemia. Interruption of cerebral blood flow results in decreased energy production, which in turn causes failure of ionic pumps, mitochondrial injury, activation of leukocytes (with release of mediators of inflammation), generation of oxygen radicals, and release of excitotoxins. Increased cellular levels of sodium, chloride, and calcium ions result in stimulation of phospholipases and proteases, followed by generation and release of prostaglandins and leukotrienes, breakdown of DNA and the cytoskeleton, and ultimately, breakdown of the cell membrane. Alteration of genetic components regulates elements of the cascade to alter the degree of injury. AMPA denotes alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and NMDA N-methyl-D-aspirate. (From Brott T, Bogousslavsky J: Treatment of acute ischemic stroke. N Engl J Med 343:710–722, 2000 with permission.)

Electroencephalogram with Chronic Renal Failure

Findings in the EEG in patients who have chronic renal failure are usually less severe than those observed in patients with acute renal failure.^[10] Several investigations have shown a good correlation between the percentage of EEG frequencies and power below 7 Hz and the decline of renal function as estimated by serum creatinine.^{[22] [42]} After the initiation of dialysis, there may be an initial period of clinical stabilization during which time the EEG deteriorates (up to 6 months) but it then approaches normal values.^[67] Still more improvement is seen in the EEG after renal transplantation.^{[42] [70]} Cognitive functions have also been shown to be impaired in uremia. These include sustained attention, selective attention, speed of decision making, short-term memory, and mental manipulation of symbols.^[10]

The causes of the EEG abnormalities observed in uremic patients are probably multifactorial but there is evidence that a very important element may be an effect of parathyroid hormone (PTH) on brain. In experimental animals with either acute or chronic renal failure, many of the EEG abnormalities can be shown to be related to a direct effect of parathyroid hormone on brain, which leads to an elevated brain content of calcium Ca²⁺.^[54] Studies in patients with either acute renal failure or chronic renal failure suggest a similar pathogenesis.^{[71] [72]}

Psychological Testing in Patients with Chronic Renal Insufficiency

Several different types of psychological tests have been applied to subjects with chronic renal failure. These have been designed to measure the effects of dialysis, renal transplantation, or parathyroidectomy.^{[25] [52] [73]}

The Trailmaking Test has been administered to a number of uremic subjects. In general, their performance was less effective than that of normal; improvement with practice limits repeated use of this test. The Continuous Memory Test correlates quite will with the degree of renal failure, as did the Choice Reaction Time. Scores in both tests improved with treatment by dialysis or renal transplantation. Similar but less impressive results are obtained with the Continuous Performance Test. Of all these tests, it appeared that the CRT was best correlated with renal function and with improvement in the patient's condition as a result of dialysis or transplantation.^{[10] [74]}

Patients who had chronic renal failure who were maintained on dialysis have been evaluated as to the possible effects of parathyroid hormone on psychological function.^[52] After establishment of baseline values, patients with chronic renal failure underwent parathyroidectomy for other medical reasons (e.g., bone disease, soft tissue calcification, and persistent hypercalcemia, all of which were unresponsive to medical management). In these patients, parathyroidectomy resulted in a significant improvement in several areas of psychological testing. They showed significant improvement in Raven's Progressive Matrices percentile scores and visual motor index (VMI) raw and percentage scores. These are tests of general cognitive function, nonverbal problem solving, and visual-motor or visual spatial skills.^{[10] [74]}

In addition, they manifested significantly fewer errors on the Trailmaking Test as well as significantly lower raw and T-score values on the Profile of Mood States Fatigue Scale postoperatively, in which they reported feeling significantly less fatigue, weariness, and inertia after undergoing surgery. Control subjects who underwent neck surgery for other reasons showed significant postoperative improvement in the Trailmaking Test but showed no change in any of the other tests.^[52] Other studies have shown that there is intellectual impairment in most patients with chronic renal failure being treated with dialysis.^{[75] [76] [77]} In these studies the procedures included the full Weschier Adult Intelligence Scale (WAIS), the Walton-Black Modified Word Learning Test (MWLT), and the Block Design Learning Test (BDLT).

The overall intellectual level, as measured by the WAIS full-scale IQ, did not differ significantly from normal. The patients' performance was due mainly to the digit symbol, block design, and picture arrangement subtests, all of which produced scores significantly below normal. The impairment of intellectual level as represented by the Wechsler deterioration quotient was also outside the normal range. The data on verbal learning obtained with the MWLT and performance learning obtained with the BDLT did not indicate any gross learning abnormality. Cognitive data were compared with other information, such as age, sex, length of dialysis, and biochemical variables by a multiple regression technique. The analysis suggested that of the cognitive data, those obtained with the BDLT bore the strongest relation to duration of dialysis. Other studies have suggested that the WAIS full-scale IQ in dialysis patients is below that of the general population.^[10] There appears to be a consensus, based on psychological testing that chronic renal failure results in organic-like losses of intellectual function, particularly information-processing capacities.^{[75] [76] [77]}

Biochemical Changes in Brain with Renal Insufficiency

To determine the possible causes of the EEG abnormalities and clinical manifestations observed in patients with renal insufficiency, in vivo biochemical studies have been carried out in brain of both patients and laboratory animals. Measurements have included brain intracellular pH and concentrations of Na⁺, K⁺, Cl^-, Al³⁺, Ca²⁺, Mg²⁺, urea, adenine nucleotides (creatine phosphate, ATP, ADP, AMP), lactate, and (Na⁺ + K⁺)-activated adenosine triphosphatase (ATPase) enzyme activity.^{[24] [65] [78] [79] [80] [81] [82] [83] [84]} In patients with acute renal failure, the brain content of water, K⁺ and Mg²⁺ is normal, whereas Na⁺ is modestly decreased and Al³⁺ is slightly elevated.^[24] However, cerebral cortex Ca²⁺ content is almost twice the normal value.^{[24] [52] [71]} Similar findings have been observed in dogs with acute renal failure.^{[54] [82]} Permeability of uremic rat brain to inert molecules (inulin, sucrose, other nonelectrolytes) is increased, whereas permeability to weak acids (sulfate, penicillin, and dimethadione) is normal to low.^{[83] [84] [85] [86]}

Alterations of cerebral metabolism that might be related to the changes in permeability mentioned earlier have also been studied in animal brain.^{[53] [79] [86] [87]} In several older studies, investigators have attempted to evaluate the effects of uremia on the central nervous system using subcellular analysis. Early studies evaluated Na-K-ATPase enzyme activity in crude microcosmal fractions obtained from brains of acutely uremic rats.^{[78] [80]} There was a significantly decreased Na-K-ATPase enzyme activity in their preparation and they suggested that the depressed enzyme activity was not due to acidosis but to the uremic state itself.^[78] On the other hand an earlier study by Van den Noort and associates^[80] found no significant difference in cationic ATPase activity in normal and uremic rat brains. In the brain of rats with acute renal failure, creatine phosphate, ATP, and glucose were increased, but there were corresponding decreases in AMP, ADP, and lactate. Total brain adenine nucleotide content and (Na⁺ - K⁺)-activated ATPase were normal to low. The uremic brain utilized less ATP and thus failed to produce ADP, AMP, and lactate at normal rates. The brain energy charge was normal, as was the redox state.^[79] There was a corresponding decrease in brain metabolic rate, along with elevated glucose and low lactate levels.^[79] Other studies of uremic brain have shown a decrease in cerebral oxygen consumption.^[43] Patients with chronic renal insufficiency (glomerular filtration rate below 20 ml/min) have decreased brain uptake of glutamine and increased ammonia uptake. The relevance of these findings, in terms of neurotransmitters or other brain function, is unknown.^[87]

In animals with either acute or chronic renal failure, both urea concentration and osmolality are similar in brain, cerebrospinal fluid, and plasma. The solute content of brain in animals with acute renal failure is such that essentially all of the increase in brain osmolality is due to an increase of brain urea concentration. However, in animals with chronic renal failure, about half of the increase in brain osmolality is due to the presence of undetermined solute (idiogenic osmoles) with the other half due to an increase of urea concentration.^{[53] [81]}

In dogs with chronic renal failure, brain content of Na⁺, K⁺, Cl^- and water are not different from control values. Similarly, the extracellular space was not different from control.^[53] Calcium content was measured in eight parts of the brain in dogs who had chronic renal failure for 4 months. Calcium content was found to be normal in the subcortical white matter, pons, medulla, cerebellum, thalamus, and caudate nucleus. However, calcium was about 60% above control values in both cortical gray matter and hypothalamus. Magnesium content was normal in all eight parts of the brain, as was water content.^[53] Other investigators have also found an elevated cerebral cortex calcium content in dogs with chronic renal failure.^[88] In animals who have acute renal failure and metabolic acidosis, the intracellular pH (pHi) of brain and skeletal muscle is normal.^[83] In dogs with chronic renal failure, intracellular pH is normal in brain, liver, and skeletal muscle.^[53] In patients with renal failure, intracellular pH has been reported to be normal in both skeletal muscle and leukocytes, as well as in the “whole body”.^{[89] [90] [91] [92]} The pH of CSF has also been shown to be normal in both patients and laboratory animals with renal failure.^{[53] [81] [83] [93]} Thus, despite the presence of extracellular metabolic acidemia in patients or laboratory animals with either acute renal failure or chronic renal failure, the intracellular pH is normal in brain, white cells, liver, and skeletal muscle.

More recently, guanidino compounds, such as methyl guanidine and guanidino succinic acid, have been shown to be neurotoxic and also to be present in several brain regions and the cerebrospinal fluid of non-dialyzed uremic patients at levels that have been shown to be experimental convulsants.^{[94] [95]}

In general then, studies of brain tissue from both intact animal models of uremia and in humans with renal failure have revealed many different biochemical abnormalities associated with the uremic state. However, such investigations have not as yet revealed much about the fundamental mechanisms that might induce such abnormalities. Such studies probably may have to be done in isolated cell systems or subcellular systems from the brain. These systems have the advantage of permitting one to study isolated manifestations of the uremic state while removing the numerous potential confounding influences present in an in vivo model.^{[82] [96]}

Cellular and Subcellular Studies

Two different cytoskeletal proteins, both early indicators of brain injury, have been examined. These included glial fibrillary acidic protein (GFAP), which is specific to astrocytes, and microtubule-associated protein-2 (MAP-2), which localizes to neuronal cell bodies and dendrites. Its loss provides one of the earliest indications of neuronal degeneration. In uremic brain (12 hours of acute renal failure), there was a diffuse increase in GFAP in cerebral cortex. Changes in MAP-2 immunoreactivity were observed in all regions of the cerebral cortex. These and other data suggest that there may be degenerative changes in neurons in brain of animals with only moderate azotemia.^[97] Studies by Fraser, Sarnacki, and Arieff^{[98] [99]} in rat brain synaptosomes demonstrated abnormalities of both sodium and calcium transport and decreased Na-K-ATPase pump activity in the brains of rats with uremia.^[98] Their findings suggested that these transport abnormalities may affect neurotransmitter release in the uremic state.^{[98] [99]} This defect did not appear to be due to the uremic environment at the time of study because nerve cell membranes were washed and frozen before study. The defect observed in uremia appeared to be due to a physical alteration of the neuronal membrane in acute uremia. These workers also demonstrated alterations of calcium transport in uremic rat brain.^[100] Based on the relationship between extracellular calcium and the release of neurotransmitter substances in nerve terminals, they concluded that this defect may affect neurotransmitter release and information processing in the uremic state. In subsequent studies, the increase in calcium transport in uremia appeared to be parathyroid hormone dependent.^{[98] [100]} Although calcium and sodium transport in synaptosomes appear to be influenced by uremia, not all transport processes are affected in this manner. Verkman and Fraser evaluated water and urea transport in synaptosomes by stopped-flow light scattering technique and found no differences in either water or urea permeabilities in normal rats compared to those with uremia.^[86] From these studies they were also able to show that synaptosomal water and urea transport occurred by a lipid diffusive pathway and was not affected by uremia.^[86]

Radiologic and Pathologic Findings in Uremic Brain

There does not currently exist a large prospective study of the radiology of uremic brain in humans.^[101] Pathologic studies of brain of patients who died with chronic renal failure are old, and there does not exist an extensive study of uremic brain that has utilized more modern pathologic methodology.^{[102] [103]} Prior to 1974, subdural hemorrhages were felt to be very common in dialyzed subjects, and were reported in about 1% to 3% of such autopsies. In addition, intracerebral hemorrhages were said to be present in about 6% of dialysis patients who died. Cerebral edema is not found in brain of patients or laboratory animals with chronic renal failure, either by biochemical or histologic criteria. Generalized but variable neuronal degeneration is often present but its anatomical location is quite variable. Among patients with uremia who have died, there is some evidence of necrosis of the granular layer of the cerebral cortex. Small intracerebral hemorrhages and necrotic foci are seen in about 10% of uremic patients, and focal glial proliferation is found in about 2%. More recently, the uremic brain has been examined using neuroimaging techniques, such as magnetic resonance imaging (MRI) and computerized axial tomography (CT).^[104]

Among patients with chronic kidney disease who are middle-aged, one third have increased cerebral white matter lesions, along with increased atherosclerosis and localized white matter ischemia.^[17] Silent cerebral white matter lesions in brain have been shown to be associated with an increased risk of stroke in a nonuremic hypertensive population.^[105] Such cerebral white matter lesions are more commonly observed in the elderly, and are also associated with an increased risk of dementia.^[106] In patients with chronic kidney disease, there is an increased prevalence of cerebral white matter lesions.^[15] In general, there is often extensive vascular calcification in brain of patients with chronic kidney disease, and this is associated with small cerebral infarcts, which are often clinically silent.^[14] The vascular calcifications in brain may be associated with the use of calcium-containing phosphate binders such as calcium acetate.^[107]

The few available studies suggest that brain of patients with uremia have a very high incidence of cerebral atrophy, which is disproportionately high for the age of the individuals studied.^{[108] [109] [110]} There appear to be subtle brain damage, not detectable by standard neuroimaging techniques or the EEG, but often manifested clinically by deterioration of intellectual capability.^{[75] [76] [111]} The recent use of advanced neuroimaging techniques has led to an increase in our understanding of changes in uremic brain in humans.^[101] Acute and subacute movement disorders have been observed in patients with end-stage renal disease (ESRD).^[112] These have been associated with bilateral basal ganglia and internal capsule lesions.^{[112] [113]} End-stage renal disease has also been reported to lead to deterioration of vision.^[114] Some cases are associated with uremic pseudotumor cerebri, and in these selected cases, surgical optic nerve fenestration may improve visual loss.^[115] There is also substantial loss of memory.^[116] Along with memory loss and decreased intellectual capability, there is also a substantial incidence of small often asymptomatic stroke, particularly in cortical white matter.^{[14] [15]} There is probably loss of neurons, which is not detectable by techniques currently in common use.

NERVOUS SYSTEM MANIFESTATIONS OF END-STAGE RENAL DISEASE

Chronic Dialysis-Dependent Encephalopathy

Despite the high overall annual mortality it is currently not unusual for patients to survive on hemodialysis for 25 years.^[117] However, among patients who have been on hemodialysis for over a decade, there is often mental deterioration, with markedly decreased intellectual capability, even without medical evidence of actual stroke.^[65] The collective syndrome of Chronic Dialysis-Dependent Encephalopathy is a combination of probable organic mental disorders plus psychiatric disorders commonly associated with hemodialysis.^[118] The exact etiology is probably multifactorial, and the important clinical manifestations are shown in Table 51-3 .

TABLE 51-3 -- Clinical Manifestations of Chronic Dialysis-Dependent Encephalopathy

Decreased intellectual capability

Impaired cognition

Chronic depression

Decreased capability for physical activity

Myopathy

Deterioration of vision

Suicidal behavior

Sexual dysfunction

Pruritus

Psychosis

Muscular weakness is an important component of Chronic Dialysis-Dependent Encephalopathy. The possible causes of weakness include conditions common in dialysis patients, such as anemia, hypothyroidism, and antihypertensive drug therapy. Such a constellation has many features in common with what has often been called uremic myopathy.^[119] Uremic myopathy is a frequent cause of weakness, exercise limitation, and rapid onset of tiredness in dialysis patients.^[120] In patients with ESRD, there is an impairment of oxidative metabolism in skeletal muscle^[121] and there is evidence that correction of acidosis by dialysis increases protein breakdown in muscle.^[122]

An important and infrequently diagnosed cause of such muscular weakness is vitamin D deficiency.^[123] Some of the clinical manifestations include muscular weakness, easy fatigue, and abnormal gait. There is also an increased tendency toward falling.^[124] There is a proximal myopathy with generalized decreased energy.^[125] The diagnostic features are a low level of vitamin D (25-hydroxy-vitamin D) and a high value for parathyroid hormone. Treatment with calciferol (10,000 units daily) and CaCO₃ (1200 mg/day) is generally effective. There is no available data about treatment of this disorder with cinacalcet (Sensipar).^[126]

Pruritus is another component of this syndrome.^[127] There has been no effective therapy for uremic pruritus, but the k-opioid receptor agonist nalfurafine shows promise.^[127]

Disturbances in sexual function are a manifestation of Chronic Dialysis-Dependent Encephalopathy.^{[12] [128]} The complications include erectile dysfunction, decreased libido, and decreased frequency of intercourse.^[129] Sexual dysfunction in men with ESRD treated with maintenance hemodialysis is common, and previously, impotence was observed in the majority of such patients.^[130] Among patients being treated with chronic hemodialysis, the current incidence of erectile dysfunction is 71% to 82%.^[131] Sexual dysfunction is also common in women who are being treated with dialsysis.^[132] It is associated with increasing age, dyslipidemia, and depression.^[133] In a comparison of woman on hemodialysis versus controls, dialysis patients had significantly poorer quality of sexual intercourse, less desire, less lubrication, and decreased ability to achieve orgasm.^[133]

There are several well-studied pathophysiologic mechanisms that probably contribute to the potential disfunction of brain tissue in patients with chronic dialysis-dependent encephalopathy. The potential mechanisms are discussed later. There are at least three important biochemical processes that have recently been explored in depth and are likely contributors to the syndrome of Chronic Dialysis-Dependent Encephalopathy (see Table 51-1 ).

Apoptosis

Apoptosis is a physiologically essential mechanism of cell death, which together with cell proliferation is responsible for the precise regulation of cell numbers for a variety of cell populations during normal development.^{[134] [135] [136]} It also serves as a defense mechanism to remove unwanted and potentially dangerous cells.^{[135] [137]} The inappropriate activation or inhibition of apoptosis, however, is now thought to cause or contribute to a variety of diseases, including cancer, stroke, brain trauma, and several neurodegenerative diseases.^{[135] [138] [139] [140]} Cell exposure to a number of pathologic entities that are present in the uremic state, such as free radicals, glutamate, hypoxia, and calcium ion (Ca²⁺)^{[43] [82] [141] [142]} can trigger both apoptosis and necrosis in the brain, two distinctly different types of cell death.^[135] The outcome of cell survival or evolution of either type of cell death can depend on the intensity of initial stimuli or a combination of type, intensity, and duration.^{[143] [144] [145]} Uremic toxins can act by altering immune function and increasing viable neutrophils, which can inhibit apoptotic removal of such cells.^[141]

A major cause of brain cell death by both apoptosis and necrosis is oxidative stress related to cerebral hypoxia/ischemia.^{[97] [146]} It has been demonstrated that brain oxygen utilization is decreased in patients with end-stage renal disease.^[43] In adults, cell death can occur by only two mechanisms—necrosis or apoptosis.^[147] A number of processes are capable of initiating apoptosis, including free radical generation, glutamate excess, hypoxic hypoxia, and calcium. All of these processes are present in the brain and CSF of patients with advanced renal failure. In addition, diabetes, the most common cause of ESRD, increases neuronal cell death by apoptosis, suggesting that diabetes itself may be an important contributor to brain cell death in patients with ESRD.^[148] Death receptors are cell surface receptors that transmit apoptotic signals initiated by specific death ligands. These death receptors belong to the tumor necrosis factor (TNF) receptor gene superfamily, and also contain a “death domain”.^[149] Activation of these death receptors inappropriately by some factor present in uremia may lead to apoptotic brain cell death. In ischemic brain tissue, the content of sodium and calcium are reduced, and this may activate apoptosis in neurons via activation of the NMDA receptor.^[150]

Oxidative Stress

A constellation of reactive intermediates—electrophiles and free radicals—capable of damaging cellular constituents is generated during normal pathophysiological proceses.^[151] The consequences of this damage include altered cell signaling, enhanced mutation rates, and accelerated neurodegeneration. In many cases, the initially generated reactive intermediates convert cellular constituents into second generation reactive intermediates capable of inducing further damage. High levels of damage can lead to cell death through apoptosis or necrosis.^[151] Uremia is associated with progressive and irreversible alterations of proteins. Reactive carbonyl compounds (RCCs) are derived from the metabolism of lipids and carbohydrates and are known to accumulate in uremia.^[152] Such compounds may play a major role in the development of uremic complications in the nervous system. The term “carbonyl stress” is a new form of uremic toxicity based on effects of such compounds.^[8] Advanced glycation end products (AGE) accumulate during the normal course of aging, and at accelerated rates in patients with diabetes and uremia. In animal models of acute renal failure, AGEs accumulate much more rapidly than expected,^[153] irrespective of the plasma glucose. They are deposited in several tissues, including skin, kidney, and blood vessels.^[154] The generation of AGEs in uremic serum has been shown to be inhibited by the presence of nitric oxide (NO) donors,^[155] and the inhibition appears to result from NO itself.^[156] A link has been established between formation of AGEs, decreased production of NO, and endothelial dysfunction in atherosclerosis.^[156] NO donors appear to be able to scavenge free radicals and suppress the formation of carbonyl compounds. The deposition in tissues of AGEs has been linked to initiation of oxidative stress via generation of reactive oxygen species. Cardiovascular disease is the major cause of death and morbidity among patients with renal insufficiency and those maintained with chronic hemodialysis.^{[16] [157]} In hemodialysis patients, there is overproduction of oxidants [reactive oxygen species (ROS), reactive nitrogen species (NRO)] compared with antioxidant defense mechanisms.^[158] Oxidative stress can lead to increased vasoconstriction in small arterioles of kidney and brain, with increased apoptotic cell death in renal tubule cells. This can be mediated by angiotensin II.^[159] Several advanced glycation end products (AGEs) are important mediators of inflammation. There is also an important inverse relationship between nutritional status and extent of inflammation and arteriosclerosis.^[160] Malnutrition is very common among dialysis patients with ESRD.^[161] The activated NAPDH oxidase complex catalyzes reduction of oxygen to super-oxide anion and then to hydrogen peroxide, which can react with halides to produce ROS in patients with chronic renal failure.^[162] Among the mechanisms that may contribute to generation of oxidative stress and increasing atherogenesis is histoincompatibility of the dialysis system, which may lead to increasing generation of ROS.^[163] There is evidence that heparin^[164] and addition of vitamin E to the dialysis membrane may help to somewhat alleviate generation of ROS.^[165] Dehydroascorbic acid may also be cerebroprotective with impending stroke.^[166] The generation of oxidants does not result simply from an accidental disruption of aerobic metabolism, but rather from an active process crucial for the nonspecific immune defenses of the brain. Although essential for survival, these processes may be inappropriately activated to cause neurodegeneration.^[97] Neurons are highly susceptible to oxidative stress, which can induce both neuronal necrosis and apoptosis. Oxidants may also have more subtle roles in compromising the integrity of the blood-brain barrier and in producing reactive changes in astrocytes that further propagate injury.^[97] Oxidative stress also appears to provide a critical link between environmental factors, such as exposure to multiple environmental factors, and genetic risk factors, in the pathogenic mechanisms of neurodegeneration. Oxidative stress appears to be a major factor in the pathogenesis of many brain disorders characterized by neurodegeneration, including Parkinson disease, Alzheimer disease, and amyotrophic lateral sclersosis.^[97] The toxicity is enhanced by inflammatory cells.

Inflammation

A chronic low-grade inflammatory condition appears to be a major factor in the generation of atherosclerosis.^[167] Plasma markers of inflammation, such as C-reactive protein (CRP) and asymmetric dimethylarginine (AMDA) are strong independent predictors of future coronary events in apparently healthy and asymptomatic individuals,^{[168] [169]} particularly women.^[160] Measurement of C-reactive protein (CRP) has been proposed as a major marker for the presence of cardiovascular disease as well as chronic inflammation.^[170] Preliminary data also suggests that CRP is particularly efficacious in predicting cardiovascular disease in women.^{[168] [171]} Elevated plasma levels of CRP may also predict renal functional loss, particularly in patients with certain co-morbid conditions, such as a high body mass index.^[172] Beta-blockers may lower C-reactive protein concentrations.^[173] By utilizing measurements of albumin and fibrinogen synthesis, and interleukin-6 production, Caglar and associates were able to demonstrate that hemodialysis itself induced an inflammatory state.^[174] The most recent data demonstrate that increasing plasma levels of CRP are associated with a 2.43-fold increase in the incidence of ischemic stroke when measured after 2 years.^[175]

Although there is substantial data relating elevated plasma levels of homocysteine to progressive atherosclerosis, there is some data that suggests that the effects of homocysteine are in fact secondary to chronic inflammation.^[176]Recent studies by Ayus and associates strongly suggest that a chronic inflammatory state in dialysis patients may lead to anemia, with resistance to erythropoietin.^{[177] [178]} In particular, Ayus and colleagues have demonstrated that the presence of an old clotted arteriovenous (A-V) graft can be a nidus for hidden infection with resistant anemia. The infected nonfunctioning A-V graft may also give rise to other severe infectious complications, such as endocarditis, pneumonia, and brain abscess.^[179] Only surgical removal of the clotted and infected graft would result in elimination of the infection or amelioration of the anemia.^{[178] [180]} Such nonfunctioning arteriovenous grafts may also occur in renal transplant recipients.^[179]

Homocysteine

Homocysteine is derived by transmethylation of methionine. Methionine is an essential sulfur-containing amino acid that is derived from protein breakdown, and it can be converted to homocysteine.^[181] Homocysteine levels in plasma increase with declining GFR. Homocysteine is involved in the pathogenesis of atherosclerosis, and it is often elevated in ESRD. Thus, homocysteine is important in the pathogenesis of arteriosclerosis in patients with ESRD who are being treated with hemodialysis, and is thus important in the development of stroke.^[182] Elevated plasma homocysteine levels are a predictor of cardiovascular mortality in patients with ESRD who are being treated with hemodialysis.^[183] However, homocysteine may be a uremic neurotoxin for several different reasons. Homocysteine activates the coagulation system and has adverse affects on the endothelium and arterial wall. The mechanism may involve the generation of reactive oxygen species and a decrease in the bioavailability of nitric oxide,^[184] which also leads to cerebral vasodilation.^[185] The decreased bioavailability of NO would result in increased generation of AGEs by uremic serum.^{[155] [156]} Additionally, homocysteine acts as an agonist at the glutamate-binding site of the NMDA receptor, allowing excessive influx of ionized calcium (Ca²⁺) and reactive oxygen generation, which can be major contributors to neuronal cell death.^[186] The incidence of stroke is substantially increased in uremic individuals maintained with hemodialysis.^[13] Homocysteine-induced oxidative stress may be only one of a number of mechanisms whereby increased arteriosclerosis is generated in uremic individuals.^{[184] [187] [188]} Even in patients who have not suffered myocardial infarction, a high plasma homocysteine level is an important predictor of congestive heart failure.^[189] The combination of uremia plus anemia is associated with an increased incidence of left ventricular hypertrophy, which can lead to congestive heart failure.^{[49] [190]}

UREMIC NEUROTOXINS IN PATIENTS WITH CHRONIC RENAL FAILURE

Central Nervous System

The number of compounds retained by the body in patients with renal failure, either singly or in combination, is substantial.^[161] Numerous studies have been carried out in order to attempt to identify which of the many compounds that are elevated in uremic subjects is truly a uremic toxin. In the early days of dialysis, so-called “middle molecules” were said to be likely candidates as uremic toxins.^[191] Although evidence was mainly observational, the concept lasted a long time.^[192] A decade later, criteria were established by Bergstom and Furst for uremic toxins. The criteria are as follows^[193]: (1) the compound should be chemically identified and quantifiable in biologic fluids, (2) the concentration of the substance in plasma from uremic subjects should be higher than that found in subjects who do not have renal insufficiency, (3) the concentration of the substance in plasma should somehow correlate with specific uremic symptoms, and these should be alleviated with reduction of the substance to normal, (4) the toxic effects of the substance should be demonstrable at concentrations found in plasma from uremic patients.

Uremic neurotoxins would imply retention of solutes that have specific detrimental effects upon nervous system function, whether peripheral nervous system or central nervous system.^{[194] [195]}

There are at least three different types of uremic solutes that are potentially toxic and that can be characterized.^[152] These include (1) small water soluble compounds, such as urea and creatinine,^[194] (2) middle molecules, (3) protein-bound compounds. Most of the small water soluble compounds, such as urea and creatinine, are not particularly toxic and are easily removed with dialysis. A low molecular weight compound for which there is increasing evidence for a role in the pathogenesis of stroke, atherosclerosis, and cardiovascular disease is asymmetric dimethylarginine (ADMA).^{[169] [196]}

Guanidine Compounds

Guanidine compounds have been postulated to be “uremic toxins” for many years,^[197] based on possible detrimental effects on the central nervous system. Recent studies have demonstrated that several guanidino compounds are present in uremic brain^[95] and may be important in the etiology of uremic encephalopathy.^[94] There are at least four guanidino compounds that are experimental convulsants. These guanidino compounds appear to work by activation of N-methyl-D-aspartate (NMDA) receptors by guanidino-succinic acid (GSA). Activation of the NMDA receptor is a major pathologic mechanism in the etiology of several types of brain damage, including head trauma^[198] and stroke.^{[199] [200]}

In addition, guanidine compounds on have a depressant effect on mitochondrial function.^[201] In brain of uremic patients, guanidino compounds were measured in 28 different regions.^[95] Guanidinosuccinic acid levels were elevated by up to 100-fold in uremic brain versus control brain, and levels increased with increasing extent of uremia. The brain levels of guanidinosuccinic acid in ureic brain were similar to those observed in normal animal brain following injection to blood levels, which cause convulsions.^[95] Guanidines inhibit neutrophil superoxide production, can induce seizures, and suppress natural killer cell response to interleukin-2.^[202] Other guanidines, which are arginine analogues, are competitive inhibitors of nitric oxide (NO) synthetase, which impairs removal of AGEs^[155] and can lead to vasoconstriction, hypertension, ischemic glomerular injury, immune dysfunction, and neurological changes.^[202] Two other low molecular weight compounds that have been recently studied appear to be important uremic toxins are diotyrosine-containing cross-linked protein products (designated AOPPs) and asymmetric dimethylarginine (AMDA).^{[169] [196]} The AOPPs behave as do mediators of inflammation and are found in very high concentration in the plasma of dialysis patients. ADMA is an inhibitor of nitric oxide and is associated with high plasma levels of homocysteine.^[196]

Middle molecules are large molecular weight compounds (300 to 12000 Daltons), which have in the past been believed to be responsible for some of the manifestations of uremia.^[203] Despite the fact that at one time, dialysis membranes were designed with the specific intent of removing more middle molecules, evidence of their toxicity is generally lacking.^{[191] [192] [193] [203] [204]} There has been some renewed interest in these molecules,^{[204] [205]} but evidence of their toxicity is still conjectural.^[202] Parathyroid hormone is a middle molecule and appears to be important in the pathogenesis of uremic encephalopathy.^[24] High plasma levels of parathyroid hormone are also associated with high levels of ischemic stroke in patients with chronic kidney disease.^[206]

With established renal insufficiency, guanidines, which are competitive inhibitors of nitric oxide (NO) synthetase, will rapidly accumulate in blood, and their presence will impair removal of AGEs^[155] and can lead to worsening hypertension, immune dysfunction,^[141] and neurological changes,^[202] such as stroke.^[207]

Advanced Glycation End Products

Advanced glycosylation (glycation) end products (AGEs) can modify tissues, enzymes, and proteins and may play a role in the pathogenesis of dialysis-associated amyloidosis.^[152] Advanced glycosylation end products may also play a role in the pathogenesis of diabetic nephropathy.^[208] Advanced glycosylation end products are markedly elevated in plasma of patients with ESRD.^[209] The AGEs react with vascular cells to inactivate endothelial nitric oxide and may increase the propensity of ESRD patients to develop hypertension. Current dialysis therapy is relatively ineffective in removal of AGEs, so that there is accumulation of AGEs in patients with ESRD, particularly those with diabetes mellitus.^[209] The AGEs are “middle molecules” and have the potential to cause tissue damage and lead to hypertension. Thus, at least some “middle molecules” may actually be deleterious in patients with ESRD, and they are poorly removed with conventional dialysis.^[209] There is evidence that angiotensin converting enzyme antagonists decrease the formation of AGEs.^[210] Protein-bound compounds (toxins) are not substantially removed by dialysis, and almost all are lipophilic. Such compounds include polyamines such as spermine.^[211] Spermine is postulated to be a uremic toxin and appears to react with the N-methyl-D-aspirate (NMDA) receptor, which affects calcium and sodium permeability in brain cells.^[211] Stimulation of the NMDA receptor in brain is the final common pathway for brain cell death in a number of pathological pathways.^{[199] [200]} The uremic state is associated with increased oxidative stress, resulting in protein oxidation products in plasma and cell membranes. There is eventual alteration of proteins with formation of oxidized amino acids, including glutamine and glutamate.^[152] Such reactions may eventually lead to stimulation of the NMDA receptor in brain, with brain cell damage or death.^[19]

Parathyroid Hormone

In patients dying with acute or chronic renal failure, the calcium content in brain cerebral cortex is significantly elevated.^{[24] [52] [54]} Dogs with acute or chronic renal failure show increases of brain gray matter calcium and have EEG changes similar to those seen in humans with acute renal failure.^{[53] [79] [82]} In dogs, both the EEG and brain calcium abnormalities can be prevented by parathyroidectomy. Conversely, these abnormalities can be reproduced by administration of parathyroid hormone to normal animals while maintaining serum calcium and phosphate in the normal range. Thus, parathyroid hormone is essential to produce some of the central nervous system manifestations in the canine model of uremia.^{[54] [88]} In addition, hyperparathyroidism in subjects with chronic renal failure is strongly associated with multiple types of cardiovascular disease, including myocardial infarction, congestive heart failure,^[223] and stroke.^[206]

Parathyroid hormone is known to have central nervous system effects in humans even in the absence of impaired renal function. Neuropsychiatric symptoms have been reported to be among the most common manifestations of primary hyperparathyroidism.^{[55] [56] [57] [58]} Patients with primary hyperparathyroidism also have EEG changes similar to those observed in patients with acute renal failure.^{[24] [224]} The common denominator appears to be elevated plasma levels of parathyroid hormone.^{[24] [52] [54] [82]} In patients with acute renal failure the EEG is abnormal within 18 hours of the onset of renal failure and is generally not affected by dialysis for periods of up to 8 weeks.^[24] In patients with either primary or secondary hyperparathyroidism, parathyroidectomy results in an improvement of both EEG and psychological testing, suggesting a direct effect of parathyroid hormone on the central nervous system. Similarly, dialysis results in a decrement of brain (cerebral cortex) calcium toward normal in both patients and laboratory animals with renal failure concomitant with improvement of the EEG.^{[24] [52] [54] [82]} In uremic patients, both EEG changes and psychological abnormalities are improved by parathyroidectomy or medical suppression of parathyroid hormone.^[52] Parathyroid hormone, a high brain calcium content, and abnormal calcium transport are probably responsible, at least in part, for some of the encephalopathic manifestations of renal failure.

The mechanisms by which parathyroid hormone might impair central nervous system function are better understood but far from complete. The increased calcium content in such diverse tissues as skin, cornea, blood vessels, brain, and heart in patients with hyperparathyroidism suggests that parathyroid hormone may somehow facilitate the entry of Ca²⁺ into such tissues. The finding of increased calcium in the brains of both dogs and humans with either acute or chronic renal disease and secondary hyperparathyroidism is consistent with the conception that part of the central nervous system dysfunction and EEG abnormalities found in acute renal failure or chronic renal failure may be due in part to a parathyroid hormone mediated increase in brain calcium. Calcium is essential for the function of neurotransmission in the central nervous system as well as a number of intracellular enzyme systems. An increased brain calcium content could disrupt cerebral function by interfering with either of these processes.^{[71] [225]}

Peripheral Nervous System

Nerve Conduction and Uremic Toxins

There are a number of solutes that are purported to impair peripheral nerve function. Several possible uremic toxins have been identified that appear to be correlated with depression of motor nerve conduction velocity (MNCV) in laboratory animals.^{[197] [212] [213]} The MNCV has become a standard test for assessment of nerve function, although it has many flaws. Most studies do not take into account the fact that (1) depressed MNCV is cyclical, with abnormal low values one day and normal values the next,^[23] (2) there is a day-to-day variation in MNCV that approaches 20%,^[214] and (3) the finding of depressed MNCV in laboratory animals associated with high plasma levels of potential uremic neurotoxins has generally not been confirmed in human subjects with renal failure.^{[191] [215] [216] [217]} Although it is possible to relate impairment in MNCV with levels in blood of various substances, the best correlation was obtained between reduced MNCV versus a reduction in glomerular filtration rate ( Table 51-4 ).

TABLE 51-4 -- Nerve Conduction and Uremic Toxins

Reference	Putative “Uremic Neurotoxin”	Correlation Coefficient with MNCV	Other
Giulio et al.^[219]	Parathyroid hormone	0.09	No effect of PTH on motor nerve function
Avram^[215]	Parathyroid hormone	0.45
Nielsen^[395]	Urea	0.41
	Creatinine	0.51
	Glomerular filtration rate	0.68–0.84
Blagg et al.^[405]	Urea	0.51
Blagg et al.^[405]	Creatinine	0.57
Blumberg et al.^[406]	Myoinositol	0.03
Reznek et al.^[217]	Myoinositol	0.67
Clements et al.^[212]	Myoinositol	Not available	Detrimental effect of myoinositol on nerve function
Man et al.^[407]	Middle molecules	Not available	No in vivo evidence of MNCV impairment with renal failure
Scribner and Babb^[203]	Middle molecules	Not available	As above
Kjellstrand et al.^[408]	Middle molecules	Not available	As above
Giovannetti et al.^[197]	Methylguanidine	Not available	Chronic injection depressed MNCV in patients
Lonergan et al.^[216]	Transketolase deficiency	Not available	Deficiency related to impaired MNCV in patients
Mahoney et al.^[53]	Parathyroid hormone	0.05	No effect of PTH on motor nerve function
Kanda et al.^[409]	Parathyroid hormone	Not available	No effect of PTH on sensory nerve function

MNCV, motor nerve conduction velocity; PTH, parathyroid hormone.

Parathyroid Hormone

It has been suggested in the past that parathyroid hormone was a peripheral nerve uremic neurotoxin, a theory based on a correlation between plasma parathyroid hormone levels and MNCV in patients with chronic renal failure.^[215]Some earlier studies suggested a possible effect of parathyroid hormone on MNCV in the dog^[213] but these impressions have not been confirmed.^[53] In patients who have hyperparathyroidism without uremia, parathyroid hormone has no observable effect on peripheral nerve function.^[218] In both patients and laboratory animals with acute renal failure, the MNCV has been found to be normal (see Table 51-4 ).^{[24] [219] [220]} In all studies of both patients and laboratory animals with chronic renal failure, the MNCV had not been shown to be affected by parathyroid hormone.^[53] Thus, in both patients and laboratory animals with either acute renal failure or chronic renal failure, or primary or secondary hyperparathyroidism, no effect of parathyroid hormone on nerve function can be demonstrated. In patients with chronic renal failure, there is no change in MNCV as a result of either recovery of renal function or chronic hemodialysis; there was also no effect of parathyroidectomy.^[219] In addition, when patients begin dialysis therapy, MNCV either stabilizes or improves.^[221] However, virtually all of these patients have elevated plasma parathyroid hormone levels.^[222]

Animal studies suggest that in either acute renal failure or chronic renal failure, changes in MNCV take longer than 6 months to develop and are probably not related to an effect of PTH. Mahoney and associates studied dogs who had renal failure for periods of 3.5 days to 6 months.^[79] There was no change in the MNCV after any of the aforementioned intervals of renal failure, and the MNCV was normal even after 6 months with glomerular filtration rate below 22% of control.

NEUROLOGIC COMPLICATIONS OF END-STAGE RENAL DISEASE AND ITS THERAPY

Dialysis Dysequilibrium Syndrome

In patients with ESRD, there are several central nervous system disorders that may occur as a consequence of dialytic therapy. Dialysis dysequilibrium syndrome (DDS) is a clinical syndrome that occurs in patients being treated with hemodialysis. The syndrome was first described in 1962^[226] and may include symptoms such as headache, nausea, emesis, blurring of vision, muscular twitching, disorientation, hypertension, tremors, and seizures.^{[227] [228]} The syndrome of DDS has been expanded to include milder symptoms, such as muscle cramps, anorexia, restlessness, and dizziness.^{[228] [229] [230] [231]} Although DDS has been reported among all age groups, it is more common among younger patients, particularly the pediatric age group.^[232] The syndrome is most often associated with rapid hemodialysis of patients with acute renal failure, but it also has occasionally been reported following maintenance hemodialysis of patients with chronic renal failure.^{[233] [234] [235] [236]} The pathogenesis of DDS has been extensively investigated and the findings are summarized elsewhere.^{[81] [228] [237] [238]} The symptoms are usually self-limited but recovery may take several days. It appears that present methods of dialysis have altered the clinical picture of DDS. Most reports of seizures, coma, and death were reported prior to 1970. The symptoms of DDS as reported in the past 25 years (1977–2002) have generally been mild, consisting of nausea, weakness, headache, fatigue, and muscle cramps. Almost all cases have occurred in patients undergoing their initial four hemodialyses. Sporadic reports of death associated with DDS do exist.^[228] However, it is unclear whether any patient ever actually died from DDS or in fact from other neurological complications associated with dialysis, such as acute stroke, subdural hematoma, subarachnoid hemorrhage, or hyponatremia.^[228] A differential diagnosis of patients presenting with these symptoms is shown in Table 51-5 . Recently, the diagnosis of DDS has become a “wastebasket” for a number of disorders that can occur in patients with renal failure and may affect the central nervous system.^[228] It is important to recognize that the diagnosis of dialysis dysequilibrium syndrome should be one of exclusion.

TABLE 51-5 -- Differential Diagnosis of Dialysis Disequilibrium Syndrome

Subdural hematoma

Uremia, per se

Acute stroke

Dialysis dementia

Cardiac arrhythmia

Dialysate composition error

Hypoglycemia

Hypercalcemia

Hyponatremia

Dialysis dysequilibrium syndrome has been treated either by addition of osmotically active solute (glucose, glycerol, albumin, urea, fructose, NaCl, mannitol) to the dialysate, or by intravenous infusion of mannitol or glycerol. Because of the technical difficulties of adding osmolytes to dialysate, this modality is seldom used. Usually, mannitol is given intravenously prior to the start of dialysis, to achieve blood levels of about 16 mmol/L. With the technique of pure ultrafiltration the patient is subjected to ultrafiltration without dialysis.^[239] The net result is loss of fluid without the patient undergoing dialysis. Ultrafiltration followed by ordinary hemodialysis has not been associated with dialysis dysequilibrium syndrome.^{[240] [241]} Dialysate and ultrafiltration profiling can greatly ameliorate many of the symptoms that are often associated with DDS.^[242] Additionally, dialysis dysequilibrium syndrome can be prevented by decreasing the time on dialysis and increasing the frequency of dialysis at the initiation of hemodialysis. Mannitol infusion accompanying the initial three hemodialyses has been successful in prevention of DDS.^[230] Administration of 50 ml of 50% mannitol both at the initiation of dialysis and after two hours of dialysis has generally been successful in preventing symptoms of DDS. The same effects can be obtained by addition of glycerol to the dialysate, but technical considerations render this option less popular.^{[231] [243]}

Chronic peritoneal dialysis is currently in use worldwide. Different types of peritoneal dialysis are carried out in-center, at home, or combinations of ambulatory plus home.^[35] Patients undergo continuous low-volume peritoneal dialysis for as long as 24 hours per day.^{[244] [245]} Symptoms of dialysis dysequilibrium syndrome have not presently been reported in patients utilizing this mode of dialysis.

Dialysis Dementia

Dialysis dementia (also called dialysis encephalopathy) is a progressive, frequently fatal neurologic disease that was initially described in several reports from 1970 to 1973.^{[102] [246] [247]} Existence of the syndrome was then independently confirmed worldwide by several different groups in the early to mid 1970s.^{[248] [249] [250] [251] [252] [253] [254] [255] [256] [257] [258] [259]} In adults, the disease has been reported almost exclusively in patients being treated with chronic hemodialysis. The early literature focused on the distinctive neurologic findings.^{[246] [247] [249] [251] [252] [260]} However, more recent reports from both Europe and the United States suggest that some forms of dialysis dementia may be a part of a multi-system disease that may include encephalopathy, osteomalacic bone disease, proximal myopathy, and anemia.^{[65] [260] [261] [262] [263]}

The etiology has largely been elucidated.^[264] Although an increase in brain aluminum content has been strongly implicated in some cases of dialysis dementia, the evidence is far less convincing in others. At this stage of our knowledge it seems useful to subdivide dialysis dementia into three categories ( Table 51-6 ): (1) an epidemic form that is related to contamination of the dialysate, often with aluminum, (2) sporadic cases in which aluminum intoxication is less likely to be a contributory factor, and (3) dementia associated with congenital or early childhood renal disease. This entity has been reported in several children who were never dialyzed or exposed to aluminum compounds. These early childhood cases may represent developmental neurologic defects resulting from exposure of the growing brain to a uremic environment.^[77]

TABLE 51-6 -- Subgroups of Dialysis Dementia

Sporadic endemic

	A.	No clear relation to aluminum intake
	B.	Worldwide distribution
	C.	No known therapy

II.

Epidemic

	A.	Geographic clusters
	B.	Often related to aluminum (Al + 3) in dialysis water
	C.	Epidemic usually stops with treatment of water supply
	D.	Probably often related to other trace elements in water, such as tin, manganese, cobalt, magnesium and iron

III.

Childhood

	A.	May be secondary to effects of uremia on the immature brain
	B.	No clear association with aluminum administration

Clinical Manifestations of Dialysis Dementia

The initial reports of dialysis dementia in the 1970s were soon followed by reports throughout the world.^[265] These patients all had the endemic form and usually had been on chronic hemodialysis for over 2 years before the onset of symptoms. Early manifestations consisted of a mixed dysarthria-apraxia of speech with slurring, stuttering, and hesitancy. Personality changes, including psychoses, progressed to dementia, myoclonus, and seizures. Symptoms initially were intermittent and were often worse during dialysis, but generally became constant. In most cases, the disease progressed to death within 6 months. Speech disturbances were found in 90% of patients, affective disorders culminating in dementia in 80%, motor disturbances in 75%, and convulsions in 60% to 90%. In contrast to this fairly distinct clinical picture, brain histology has generally been normal or nonspecific.

Early in the disease, the EEG shows multifocal bursts of high amplitude delta activity with spikes and sharp waves, intermixed with runs of more normal appearing background activity. These EEG abnormalities may precede overt clinical symptoms by 6 months. As the disease progresses, the normal background activity also deteriorates to slow frequencies.^[232] The EEG has been said to be pathognomic, but a similar pattern may also be seen in other metabolic encephalopathies. The diagnosis depends on the presence of the typical clinical picture and is confirmed by the characteristic EEG pattern.^[252] Magnetoencephalography (MEG) has only recently been used in the evaluation of uremic patients.^[266] MEG has not yet been used in the evaluation of patients with dialysis dementia.

Aluminum and Dialysis Dementia

Aluminum intoxication was first implicated in this disorder by Alfrey and associates.^[255] Aluminum content of brain gray matter was elevated to 11 times the normal value in patients with dialysis dementia, versus an increase of three times normal in patients on chronic hemodialysis without dialysis dementia. Aluminum content was also increased in bone and other soft tissue. Oral phosphate binders containing aluminum {Al(OH)₃ and Al₂(CO₃)₂} were originally suspected as the source of the aluminum.

Most of the aluminum in blood is bound to transferrin, so that the blood contains very little free aluminum.^[267] The brain contains few transferrin receptors, so that normally, aluminum uptake into brain is negligible. Any free aluminum in blood, usually in the form of aluminum-citrate, can readily enter the central nervous system. Aluminum binding can be studied with the aluminum analogue gallium.^[268] Normally, there is an excess of gallium-binding sites in plasma, so that even in situations where blood aluminum is increased, there is still almost no free aluminum in blood. In studies of gallium-transferrin binding in blood of patients having either Alzheimer disease, Down syndrome, or renal failure treated with chronic hemodialysis, gallium binding to transferrin was significantly reduced in patients with either Down syndrome or Alzheimer disease.^[267] However, gallium binding to transferrin was normal in patients with chronic renal failure treated with hemodialysis. In such patients, there was accumulation of aluminum in those brain regions with high densities of transferrin receptors.^[267]

The aforementioned findings involve studies in only small numbers of subjects with dialysis dementia (n = 9)^{[267] [269]} or chronic renal failure treated with hemodialysis (n = 5). More such studies are needed before it can be conclusively stated that the distribution of aluminum in brain of patients with dialysis dementia is not similar to that in patients with Alzheimer disease. In patients with chronic renal failure without dialysis dementia, neurofibrillary changes are not present.^{[102] [103]}

Recent studies have further added to our knowledge of the possible effects of aluminum on the central nervous system in patients with chronic renal failure. A possible pathophysiologic basis for detrimental effects of aluminum on the central nervous system has been described by Altmann and associates.^[270] Dihydropteridine reductase is an important enzyme in the synthesis of several important neurotransmitters, such as tyrosine and acetyl choline. They found that erythrocyte levels of dihydropteridine reductase activity were less than predicted values, and correlated with plasma aluminum levels.^[270] After treatment with desferrioxamine, red cell dihydropteridine reductase activity levels doubled. Although brain levels of dihydropteridine reductase activity were not evaluated, it was suggested that high brain aluminum levels might lead to decreased availability of dihydropteridine reductase in the brain. It has been suggested that merely the presence of an increased body aluminum burden has an adverse effect on overall mortality.^[271] More specifically, an increased body aluminum burden (estimated by the desferrioxamine infusion test) has been associated with memory impairment and increased severity of myoclonus with decreased motor strength.^[272]

Altmann and associates evaluated patients with chronic renal failure and apparently normal cerebral function performance.^{[270] [273]} They found that when compared to a control group with similar IQ, the patients with chronic renal failure had abnormalities in six tests of psychomotor function. Plasma aluminum levels were only mildly elevated (59 ± 9 mgm/l). When 15 of these patients were treated for 3 months with desferrioxamine, anemia improved and the erythrocyte activity of dihydropteridine reductase rose significantly. Changes in erythrocyte dihydropteridine reductase activity correlated significantly with changes in psychomotor performance.^{[270] [273]} Even at high blood Al levels, most Al is bound to transferrin^[267] and thus cannot bind to the cerebral transferrin receptors. It may be that patients who develop dialysis dementia have less transferrin binding capacity, less transferrin, or a greater density of transferrin receptors in the brain. These issues have not been studied to date.

Toxic Manifestations of Aluminum on the Central Nervous System

Thus, aluminum may be potentially toxic in patients with chronic renal failure, possibly leading to both dialysis dementia and osteomalacia.^{[253] [254] [261] [262] [263]}

Most nephrologists would agree that the potential hazards of poor control of plasma phosphate are worse than the potential toxicity of aluminum accumulation from oral aluminum-containing antacids. However, recent studies suggest that calcium carbonate (or acetate) may be more effective for the control of hyperphosphatemia than is aluminum hydroxide.^{[274] [275]} More recently, sevelamer (Renagel®, Genzyme Corp, Cambridge, MA), a polymeric phosphate binder, has come into wide usage for control of phosphate in chronic dialysis patients.^[276] Renagel®, although expensive, has been found to be more effective than calcium carbonate, calcium acetate, or aluminum hydroxide for the management of hyperphosphatemia in dialysis patients,^[276] and it does not introduce aluminum into the body. However, aluminum is still the second most prevalent element in the earths crust, and a substantial quantity will enter the body, even without administration of aluminum-containing antiacids.^{[277] [278] [279]} Lanthanum carbonate (Fosrenol®) is a new agent for the management of hyperphosphatemia in patients with ESRD.^[280] It has been extensively tested in humans and is capable of maintaining plasma phosphate levels at levels recommended by K/DOQI.^[281] It is far more expensive than calcium-based phosphate binders and thus far has proved most useful in patients unable to tolerate sevelamer. It is too early to tell how useful it will eventually be in the control of hyperphosphatemia in patients with ESRD.^[281] Compared to sevelamer, the pills are much smaller and are taken less often (1 small pill three times daily versus 2 large pills four times daily).

Deionization of the water used to prepare dialysate has recently become a standard procedure, as well as a preventive measure for dialysis dementia.^{[282] [283]} However, deionization may be beneficial by removing any number of other agents from dialysis water. Other trace elements may be present in water, which can result in central nervous system toxicity. Such elements include cadmium, mercury, lead, manganese, copper, nickel, thallium, boron, and tin. Among these potentially neurotoxic elements no one has measured brain content of cadmium, mercury, nickel, thallium, vanadium, or boron. Manganese has been found to be increased in cortical white matter in the eight encephalopathic patients in whom it was measured.^[259] These patients also had elevated aluminum levels in gray matter.

Most of the controversy over the etiology of dialysis dementia has involved those cases that occur sporadically. As noted previously, dialysate aluminum levels are not always elevated. The use of aluminum-containing antacids in the past was no different in patients with dialysis dementia than in unaffected patients, and brain aluminum levels in patients with dialysis dementia generally overlap with those of unaffected patients.^[264] The largest group of “sporadic cases” has been reported from Nashville, Tennessee.^[261] The reported incidence of dialysis dementia in the area is 5%, despite the use of deionized water for dialysate with aluminum levels below 5 mg/L. Osteomalacic bone disease was not clinically apparent in this group. Serum aluminum levels in the encephalopathic group were three to four times higher than other dialyzed patients, despite equivalent prescribed doses of aluminum-containing phosphate binders. These results suggest greater absorption and/or retention of aluminum or other trace metal contamination in this group of encephalopathic patients. No other metals were measured in the Nashville study.

The evidence available thus far indicates that aluminum is elevated in the brain (cortical gray matter) of patients with dialysis dementia. However, the actual contribution of aluminum to the encephalopathy remains unclear. Aluminum content has been reported to be elevated in the brain of patients with other disorders, including senile dementia and Alzheimer syndrome, and might actually be a nonspecific finding associated with dementia. Aluminum is also elevated in the brains of patients who have other disorders associated with altered blood-brain barrier. Such disorders include renal failure, hepatic encephalopathy, and metastatic cancer. Other evidence suggests that brain aluminum content may also increase as a function of the aging process. Thus, blood-brain barrier abnormalities can result in increased brain aluminum content.^[284]

Prevention and Therapy of Dialysis Dementia

Despite these unresolved questions, most past outbreaks of the epidemic form of dialysis dementia have been associated with high levels of aluminum in the dialysate.^{[253] [285] [286]} Lowering the dialysate aluminum to below 20 mg/L, usually by deionization, appears to prevent the onset of the disease in patients who are beginning dialysis. New cases may continue to appear in those patients who were previously exposed to the high aluminum dialysate, although the course is milder and mortality is somewhat decreased. In patients with overt disease, eliminating the source of aluminum has resulted in improvement in some but not all patients. Renal transplantation has generally not been helpful in patients with established dialysis dementia. Diazepam or clonazepam are useful in controlling seizure activity associated with the disease, but become ineffective later on and do not alter the final outcome.^[251]Because the treatment of dialysate water with deionization has become standard (in the United States, Western Europe, and Israel), epidemic dialysis dementia has become increasingly rare.

Treatment of sporadic cases, in which the etiology is not clear, is more difficult. Every effort should be made to identify a treatable cause. Dialysis dementia must be differentiated from other metabolic encephalopathies, such as hypercalcemia and hypophosphatemia, hyperparathyroidism, acute heavy metal intoxications and structural neurologic lesions, such as subdural hematoma ( Table 51-7 ).^[287] Because of the low incidence, the uncertain etiology, and the poor correlation of plasma with tissue aluminum levels, screening tests have not generally been employed.

TABLE 51-7 -- Differential Diagnosis of Dialysis Dementia

Metabolic encephalopathies

	A.	Hypercalcemia
	B.	Hypophosphatemia
	C.	Hypoglycemia
	D.	Hyperosmolality
	E.	Hyponatremia
	F.	Symptomatic uremia
	G.	Drug intoxications
	H.	Trace metal intoxications
	I.	Hyperparathyroidism

II.

Hypertensive encephalopathy

III.

Dialysis disequilibrium

IV.

Structural lesions of the brain

	A.	Subdural hematoma
	B.	Normal pressure hydrocephalus
	C.	Stroke

The source of excess Al³⁺ in brain is not entirely clear. Some Al³⁺ apparently is absorbed after oral administration of aluminum-containing antacids.^{[37] [141]} Significant absorption of oral aluminum can occur in patients with chronic renal failure but the weight of evidence is against oral aluminum as an important source of aluminum in brain. The retention of Al³⁺ after oral administration of Al³⁺ salts is greater in patients with renal failure than in normal subjects.^{[288] [289]} The typical daily dietary Al³⁺ intake is 10 to 100 mg,^[279] although absorption is normally minimal. This quantity of dietary Al³⁺ is more than enough to account for the entire increase of brain Al³⁺observed in patients with dialysis dementia. Among 22 such patients, the mean brain Al³⁺ content was 22 mg/kg dry weight. The normal human brain weighs about 1500 gm and is about 80% water, or 300 gm dry weight. Thus, the total increase in Al³⁺ content for the whole brain is less than 7 mg in patients with dialysis dementia. Therefore, the entire increase of brain Al³⁺ in such patients can theoretically be accounted for by dietary aluminum.^[264] The increase in body aluminum stores may also be, in part, the result of Al³⁺ contamination from other sources, such as Al³⁺ in dialysate water, dialysis system aluminum pipes, or aluminum leaked from anodes.^[264]

Brain Lesions and Dialysis Dementia

There are a large number of children who have renal insufficiency and also require hospitalization with intravenous therapy. Such children may receive large quantities of intravenous aluminum (Al³⁺) from contamination of intravenous solutions with aluminum salts.^{[290] [291] [292] [293] [294] [295]} Thus, even in the absence of hemodialysis therapy, children with chronic renal failure may receive large quantities of intravenous aluminum, which may explain the development of dialysis dementia even in the absence of dialysis.^[295] The location of the aluminum in brain of patients with dialysis dementia has not been well established. In Alzheimer disease, it initially appeared that the aluminum was localized only to the nuclear regions of neurofibrillary tangles.^[296] More recent investigations reveal that in Alzheimer disease, aluminum accumulates in at least four different sites: DNA containing structures of the nucleus; protein moieties of neurofibrillary tangles; amyloid cores of senile plaques; and cerebral ferritin.^{[297] [298] [299]}

Senile plaques and neurofibrillary tangles are of course diagnostic features of Alzheimer disease.^[300] It is not generally appreciated that in dialysis dementia, the brain also contains senile plaques and neurofibrillary tangles in the majority of cases.^[269] However, in dialysis dementia, aluminum was not located in the neurons but rather, in glial cells and the walls of blood vessels.^[282] The aforementioned findings involve studies in small numbers of patients (chronic renal failure treated with hemodialysis = 5; dialysis dementia = 9).^{[267] [269]} More such studies are needed before it can be conclusively stated that the distribution of aluminum in brain of patients with dialysis dementia is not similar to that in patients with Alzheimer disease.

Deionization of the water used to prepare dialysate has recently been employed as a preventive measure.^[282] However, deionization may be beneficial by removing any number of other agents. Other trace elements may be present in water, which can result in central nervous system toxicity. Such elements include cadmium, mercury, lead, manganese, copper, nickel, thallium, boron, and tin.^[301] Among these potentially neurotoxic elements no one has measured brain content of cadmium, mercury, nickel, thallium, vanadium, or boron. Manganese has been found to be increased in cortical white matter in the eight encephalopathic patients in whom it was measured.^[259] These patients also had elevated aluminum levels in gray matter.

Treatment of sporadic cases, in which the etiology is not clear, is more difficult. Every effort should be made to identify a treatable cause. Dialysis dementia must be differentiated from other metabolic encephalopathies, such as hypercalcemia and hypophosphatemia, hyperparathyroidism, acute heavy metal intoxications and structural neurologic lesions, such as subdural hematoma (see Table 51-7 ).^[287] Because of the low incidence, the uncertain etiology, and the poor correlation of plasma with tissue aluminum levels, screening tests have not generally been employed.

The source of the increased Al³⁺ in brain of patients with dialysis encephalopathy can theoretically be accounted for on the basis of increased Al³⁺ intake. However, it is unclear as to how the Al³⁺ enters brain in increased quantities. It may be that the increased body aluminum burdens present in uremic subjects may contribute to increased Al³⁺ content in brain of such individual. To clarify the role of oral ingestion of aluminum salts in the causation of increased brain Al³⁺ content, it would be instructive to examine brain tissue from patients without renal failure who had ingested large quantities of Al(OH)₃ (i.e., patients with chronic peptic ulcer disease). However, because such material is not likely to be available, studies in laboratory animals given large quantities of aluminum salts should provide similar information. In both rats and dogs receiving oral aluminum salts, there is a significant increment in brain Al³⁺ content.^{[258] [302] [303]} Administration of parathyroid hormone to rats receiving aluminum salts results in an additional increment of brain Al³⁺ content.^{[288] [303] [304]} Thus, in laboratory animals, both a chronic increase in oral Al³⁺ ingestion, or parathyroid hormone excess, can lead to an increase of cerebral cortex Al³⁺, even in the absence of renal failure.

Alternative Etiologies

Many other possible causes of dialysis dementia have been proposed. These include other trace element contaminants,^{[247] [264] [303]} normal pressure hydrocephalus,^[264] slow virus infection of the central nervous system,^[192] and regional alterations in cerebral blood flow.^[305] Some patients with dialysis dementia may have altered cerebrospinal fluid dynamics, which are at least suggestive of normal pressure hydrocephalus.^[306] Six patients with dialysis dementia were found to have normal cerebrospinal fluid dynamics, but only mild dilatation of the cerebral ventricles.^[306] In this study, however, control subjects (uremic patients treated with hemodialysis but not having dialysis dementia) were not evaluated, and results of recent studies suggest that many patients who have end-stage renal disease without dialysis encephalopathy may also have ventricular dilatation with cerebral atrophy.^[307] Furthermore, there is a generally poor correlation between ventricular dilatation, cerebral atrophy, and the presence of dementia.^[308]

Slow virus infection of the nervous system is a possible etiology for dialysis dementia. The clinical manifestations resemble those of other slow virus infections, such as Kuru or Creutzfeldt-Jakob disease.^{[309] [310]} In at least one instance, a slow virus (foamy virus) has been isolated from the brains of patients who died with dialysis encephalopathy.^[309]

In summary, dialysis dementia probably represents an end point in a disease of multiple etiology. There are at least three subgroups and in two of them the etiology of dialysis encephalopathy must be regarded as unknown. The possible role of aluminum, or other trace element abnormalities, is unclear. At this time, there is no known satisfactory treatment for patients with dialysis encephalopathy. Most patients reported in the literature thus far have not survived, usually dying within 18 months of the time of diagnosis. The syndrome is not alleviated by increased frequency of dialysis, and usually not by renal transplantation.^{[260] [301]} Definitive therapy must await a better understanding of the pathogenesis of this disorder. The use of deferoxamine to chelate aluminum or other trace elements is experimental and currently under extensive investigation. There have been several reports of improvement in patients with dialysis dementia treated with deferoxamine,^{[306] [311]} but these results have not been confirmed.

OTHER CENTRAL NERVOUS SYSTEM COMPLICATIONS OF DIALYSIS

In addition to dialysis dementia and dialysis dysequilibrium syndrome, there are several other neurological disorders that have been reported in patients being treated with dialysis. In most instances, patients have initially presented with headache, nausea, emesis, or hypotension, whereas some have had seizures. Most such patients have initially been diagnosed as having DDS, whereas others, particularly those with chronic subdural hematoma, have been suspected of having dialysis dementia. The disorders include copper intoxications, subdural hematoma, muscle cramps, nonketotic hyperosmolar coma with hyperglycemia, cerebral embolus secondary to shunt declotting, acute cerebrovascular accident, depletion syndrome, malfunction of fluid proportioning system, excessive ultrafiltration with hypotension and seizures, hypoglycemia, and Wernicke encephalopathy.^{[53] [74]} In the past, cerebral complications were the second most frequent cause of death among patients being treated with hemodialysis.^[312]

Subdural Hematoma

Subdural hematoma is currently an infrequent cause of death in patients maintained with chronic hemodialysis.^[72] This condition may initially present with headache, drowsiness, nausea, and vomiting. If the patient loses consciousness or develops signs of increased intracranial pressure, a diagnosis of subarachnoid bleeding should be considered. Such episodes in uremic patients are usually fatal unless operated on. If these symptoms persist between hemodialysis, or progressively worsen, subdural hematoma is likely, particularly if the patient is taking anticoagulants. On physical examination, there is often evidence of localized neurological disease; there may be signs of meningeal irritation, and somnolence and focal seizures may be observed. The diagnosis can usually be made by modern neuroimaging techniques [computed axial tomography (CAT scan) or magnetic resonance imaging (MRI)].^{[101] [313]} Subarachnoid bleeding in hemodialysis patients is probably often related to anticoagulant excess.^[314] The initial symptom when intracranial hemorrhage occurs is usually depression of sensorium: convulsions may follow and the patients may lapse into coma.

Technical Dialysis Errors

Improper proportioning of dialysate, due to either human or mechanical error, was once an important cause of neurological abnormality in dialysis patients.^[315] The usual effect of such dialysate abnormalities is the production of either hyponatremia or hypernatremia. Both of these abnormalities of body fluid osmolality can lead to seizures and coma, although different mechanisms are involved. In acute hypernatremia, there will be excessive thirst, lethargy, irritability, seizures, and coma, with spasticity and muscle rigidity. In acute hyponatremia there is weakness, fatigue, and dulled sensorium, which may also progress to seizures and coma, respiratory arrest, and death. Such symptoms developing soon after initiation of hemodialysis should alert the physician to the possibility of such an error. A check of the dialysate osmolality or sodium concentration is the most rapid means of detecting this problem. Death has been reported as a consequence of either hypernatremia or hyponatremia.^{[316] [317]} Technical errors are fortunately rare in the twenty-first century.

About one liter of fluid per hour can be removed by ultrafiltration hemodialysis, and about 300 ml/hr by peritoneal dialysis using hypertonic dialysate. Such a rate of fluid removal from the intravascular space may be faster than the rate at which fluid can be replaced from the interstitial compartment, and hypotension may develop. Symptoms of hypotension may include seizures that, although actually due to cerebrovascular insufficiency, may be mistaken for DDS, particularly in diabetic subjects.

Most of the neurologic complications of renal transplantation relate to secondary afflictions, such as infection and neoplasia. As already discussed, most of the neurologic complications of the uremic state tend to improve following renal transplantation. These include the neuropathy, encephalopathy, and EEG changes.^{[318] [319] [320]}

STROKE IN PATIENTS WITH RENAL INSUFFICIENCY TREATED WITH HEMODIALYSIS

Mechanisms of Cell Damage with Stroke

The incidence of stroke among dialysis patients in the United States is 28 inpatient events per 1000 patient years at risk for ages 45 to 64 years.^[27] The figure rises to 76 for individuals above age 65 years.^[27] When uremic patients maintained with chronic dialysis suffer a possible stroke, brain neuroimaging, using CT or MRI is likely to be carried out for diagnostic purposes. However, as yet, a series of such neuroimaging cases has not been assembled for research purposes. Acute ischemic stroke (cerebrovascular accident, CVA) is a condition where a portion of the brain is acutely deprived of sufficient blood flow. The brain requires about 50 cc/mL/min of blood that contains an adequate level of glucose and oxygen to function normally.^[321] Acute ischemic stroke can be subdivided into three different mechanisms—decreased systemic perfusion, thrombosis, and embolism. Decreased systemic perfusion implies cardiopulmonary insufficiency (hypoxic ischemia), usually due to myocardial infarction, arrhythmia, or hemorrhage. Systemic hypoperfusion will not cause an acute ischemic stroke and is discussed elsewhere.^[322]Thrombosis refers to blockage of blood flow due to a localized in situ occlusive process within one or more blood vessels. The most common vascular pathology is atherosclerosis. Fibrous and muscular tissue overgrow in the subintima, and fatty materials form plaques that can encroach on the lumen. Next, platelets adhere to plaque crevices and form clumps that serve as nidi for the deposition of fibrin, thrombin, and clot.^[321] Plaque rupture can activate the coagulation cascade, leading to formation of an occlusive thrombus. Another important possibility would be acute hemorrhagic stroke, where there is actual rupture of a vessel, with bleeding into the substance of the brain, followed by secondary tissue ischemia. Brain damage following occlusion of a blood vessel is mediated by several biochemical mechanisms.

Excessive amounts of glutamate in brain extracellular fluid initiate at least a part of the pathogenesis for brain damage in ischemic states.^[322] Ischemia causes a release of glutamate into cerebral extracellular space, leading to excitation of a subset of glutamate receptors, the N-methyl-D-aspartate (NMDA) receptor. Hypoxia increases excitation in neurons, particularly at the NMDA receptor. Excitation at this receptor then leads to an excessive influx of sodium ions and water.^[200] Excitation, or increased synaptic activity, is an important factor in eventual cell death in hypoxic neurons.^[198] Thus, the classical biochemical teachings where hypoxia/ischemia leads to a decrease of brain high energy phosphate compounds, with a secondary influx of sodium, chloride, and water into brain are probably incorrect.

A point is eventually reached where cerebral edema has occurred and cell viability is severely compromised. If the cellular damage continues, there follows an influx of calcium ions and a probable decrease in intracellular magnesium,^[323] which is at some point followed by permanent neuronal damage. The actual event that leads to irreversible cell death in hypoxic brain is not entirely clear. A late event is the movement into hypoxic cells of calcium, and in certain types of cell injury, calcium overload is the actual pathogenetic mechanism.^[324] There are a number of theoretical reasons why calcium overload may be detrimental to cells. An increase in free cytosolic calcium can activate calcium-dependent phospholipases, resulting in the breakdown of cell membranes and production of substances that are toxic to cells, such as free fatty acids and phosphospholipids.

Demographics of Stroke in Patients with Renal Insufficiency

Uremic patients are prone to several risk factors that have a tendency to be associated with a high incidence of stroke ( Table 51-8 ). Such factors include diabetes mellitus, uremia, hyperparathyroidism, a smoking history, hypertension, elevated cholesterol and triglycerides, elevated C-reactive protein, atherosclerosis, hemodialysis therapy, and use of over-the-counter vasoactive drugs.^{[13] [177] [206] [325] [326] [327]} Patients with chronic kidney disease appear to have a chronic inflammatory state, which is multifactorial in origin. Recently, substantial data has accumulated demonstrating that inflammation, particularly a chronic inflammatory state, greatly increases the risk of stroke.^{[17] [160]} From a clinical standpoint, cerebrovascular disease is a common cause of death in chronic hemodialysis patients^[187] and stroke represents the second most frequent cause of death.^{[13] [187] [328]} (The three most frequent causes are heart attack, stroke, and infection.^[329]) In the United States and Western Europe (including Israel), cardiovascular disease is far more common in dialysis patients than in the rest of the population.^{[18] [330]} Part of the reason may be that the major cause of end-stage renal disease in the United States is diabetes mellitus (27%), far more than in Europe (19%) and Japan (10%).^{[331] [332]} Among the factors that doubtless contribute to the high incidence of stroke in patients with ESRD treated with hemodialysis are the high incidence of hypertension and smoking, both of which are higher in ESRD patients than in the rest of the population. There is also the large number of such patients who have diabetes mellitus and the accelerated arteriosclerosis in diabetic patients.^[333] In addition, uremic patients tend to have high cholesterol levels and a high incidence of obesity, and they tend to smoke cigarettes more than does the rest of the population.^{[334] [335]} There is a high incidence of chronic infection in dialysis patients, which leads to elevated blood levels of atherogenic risk factors, such as cytokines, which appear to contribute to the increased incidence of stroke in such patients.^{[177] [180] [336]} The elevated cytokines are largely due to the high incidence of chronic inflammatory conditions in chronic hemodialysis patients.^[177] Part of the high incidence of an inflammatory state among patients with chronic kidney disease may come from the process of hemodialysis itself.^[174]

TABLE 51-8 -- Important Risk Factors for Stroke

Diabetes mellitus

Uremia

Hyperparathyroidism

Smoking history

Hypertension

Elevated cholesterol

Elevated triglycerides

Elevated C-reactive protein

Atherosclerosis

Hemodialysis therapy

Elevated homocysteine

Diabetes mellitus is now the most common cause of chronic kidney disease in the United States. One of the components of type II diabetes and metabolic syndrome is the presence of insulin resistance.^[337] Both insulin resistance and metabolic syndrome lead to a clinical state of inflammation, which worsens cerebral vascular disease and increases the incidence of stroke.^[338] Overall, stroke and myocardial infarction are the important causes of death in patients with chronic kidney disease (CKD). The most important risk factors remain the traditional ones—hypertension, obesity, smoking, diabetes, and limited physical activity.^[339] Nontraditional risk factors, including anemia, elevated C-reactive protein, interleukin (log), and cystatin C also predicted increased cardiovascular mortality, but were less important.^{[339] [340] [341]}

Chronic Inflammation and Cerebrovascular Disease

An outpouring of data recently has pointed to the presence of a chronic low-grade inflammatory condition as a major factor in atherosclerosis leading to stroke.^[167] Plasma markers of inflammation, such as C-reactive protein (CRP), asymmetric dimethylarginine (AMDA), and reactive carbonyl compounds (RCCs) are strong independent predictors of future coronary or cerebral events in apparently healthy and asymptomatic individuals,^[196] particularly women.^{[160] [168] [171]} Both AMDA and RCCs are known to accumulate in uremia.^[152] Elevated plasma levels of CRP may also predict renal functional loss, particularly in patients with certain co-morbid conditions, such as a high body mass index.^[172] Beta-blockers may lower C-reactive protein concentrations.^[173] By utilizing measurements of albumin and fibrinogen synthesis, and interleukin-6 production, Caglar and associates were able to demonstrate that hemodialysis itself induced an inflammatory state.^[174] The most recent data demonstrate that increasing plasma levels of CRP are associated with a 2.43-fold increase in the incidence of ischemic stroke when measured after 2 years.^[175]

THERAPY OF STROKE

The management of acute stroke has lagged far behind that for myocardial infarction. Aside from supportive therapy, specific treatments are poorly developed and are insufficiently utilized. Angioplasty in patients with acute stroke is uncommon and data of its efficacy is scarce.^[343] For carotid insufficiency, data is available on the effects of stent placement before a stroke occurs.^[344] The use of hyperbaric oxygen therapy in patients with acute stroke has thus far not demonstrated any improvement in morbidity.^[345] Antiplatelet therapy has been widely used for the prevention of secondary stroke, particularly in patients with transient ischemic attack (TIA). The main drugs utilized are aspirin, dipyridamole, and clopidogrel.^[346] All have some efficacy, but unfortunately, both aspirin and clopidogrel are often complicated by bleeding problems, especially when used in combination. Data is accumulating and the indications are still not resolved. The use of thrombolysis (tissue plasminogen activator) in patients with acute stroke has been extensively studied in patients with myocardial infarction. However, the use of tissue plasminogen activator in patients with acute stroke is highly controversial, with the indications not at all clear.^[347] Following the use of thrombolysis in acute stroke, arterial recanalization is augmented by continuous transcranial Doppler.^[348] It does appear that in patients who have had an ischemic stroke, the risk of a subsequent stroke or myocardial infarction is substantially increased.^[349] Ischemia leading to stroke only initiates biochemical events that may ultimately lead to brain damage. There exist interventions that can counter these biochemical events. Such interventions should theoretically decrease the brain damage associated with acute stroke, but actual data in this regard is far from complete at this time.^{[146] [350]}

Chronic Inflammation and Cardiovascular Disease

Advanced glycosylation end products (AGEs) can modify tissues, enzymes, and proteins and may play a role in the pathogenesis of dialysis-associated amyloidosis.^{[8] [152] [351]} Advanced glycosylation (glycation) end products are markedly elevated in plasma of patients with ESRD,^[8] particularly if they also have diabetes mellitus.^[332] These AGEs react with vascular cells to inactivate endothelial nitric oxide and may increase the propensity of ESRD patients to develop arteriosclerosis and hypertension.^[209] There is evidence for increased cytokine production secondary to blood interaction with bioincompatible dialysis components. In particular, blood-dialyzer interaction can activate mononuclear cells, leading to production of inflammatory cytokines.^[162] Synthetic high-flux dialyzer membranes are permeable to the pro-inflammatory cytokines, and are capable of removing interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6, thus offering a potential therapeutic approach.^[163] It is unclear whether cytokine removal by continuous renal replacement therapy will decrease the incidence of stroke.^[352] The use of sorbents with continuous plasma filtration offers another possibility for a novel therapeutic approach.^[352] Some of the cytokines, such as interleukin-1β (IL-1 b), TNF-α, and interleukin-6, may induce an inflammatory state, and are believed to play an important role in dialysis-related mortality.^[336] Recent prospective studies have demonstrated that patients with ESRD and higher blood levels of certain cytokines have a greater mortality and have a larger number of cardiovascular events. In fact, elevated levels of markers of inflammation are associated with increased mortality and decline in function in elderly patients without ESRD.^[353] However, just the presence of renal insufficiency, even with GFR of 70 ml/min, can result in an increased risk of myocardial infarction and death.^[354] Contaminated dialysate water can result in pyogenic substances of bacterial origin being absorbed into the dialysis membrane.^[163] The consequence could be induction of an inflammatory response in certain dialysis patients. Substances of bacterial origin activate circulating mononuclear cells to produce proinflammatory cytokines. The effects of dialysis reuse on cytokine production has not been evaluated, but may be important, as reuse could theoretically lead to more contamination of dialysate.^[163] Reactive carbonyl compounds and AGEs, which tend to modify proteins in a deleterious manner,^[152] can be decreased by use of a peritoneal dialysate containing icodextrin and amino acids instead of glucose.

Cerebral ischemia initiates a number of processes that can lead to progressive brain damage.^[355] Cerebral ischemia can lead to activation in brain of free radicals, N-methyl-d-aspartate,^[356] and apoptosis,^[147] all potential mechanisms of brain damage in patients with hypoperfusion or stroke (see Fig. 51-1 ).^{[136] [143] [144]} Anoxic injury to brain endothelial cells can increase production of nitric oxide, which can increase free radical formation.^{[357] [358]} In general, the ischemic event of a stroke only serves to initiate the biochemical events that may lead to brain damage. Interventions that counter these biochemical events may decrease the brain damage associated with acute stroke.^{[146] [350]}

Prevention of Stroke

Recent knowledge of the pathogenesis of stroke has led to a major expansion in the opportunities for prevention of stroke. Some of the simplest and most important strategies are shown in Table 51-9 . High-grade carotid stenosis can lead to stroke, although the exact numbers of patients who will suffer stroke when they have carotid stenosis is not known. Screening patients who have renal failure for the presence of carotid stenosis will diagnose a substantial number of such patients, although at considerable cost. However, because of noninvasive diagnostic techniques such as duplex Doppler ultrasonography, screening for carotid stenosis involves essentially no morbidity.^[146] Studies of the aortic arch for the presence of large atherosclerotic plaques (more than 4 mm thick) is an important predictor for the possibility of stroke in the future,^[359] as is the presence of atrial fibrillation, both for initial strokes^{[327] [360]}and recurrent stroke.^[361] Transient ischemic attacks are often associated with numbness, weakness, or even partial blindness. Such symptoms occur in patients with ESRD, particularly if they also have diabetes mellitus. It is not generally appreciated that they are often the harbinger of stroke.^[360] The presence of such a symptom complex should trigger a work-up that includes evaluation of the carotids (ultrasound, CT, or MRI). Migraine is a common clinical disorder, often characterized by an aura, headache, and autonomic dysfunction.^[362] In patients with ESRD, headache is common, and the possible association with impending stroke may not be appreciated. Other common preventive measures include management of hypertension, cessation of smoking, lowering of plasma cholesterol, control of plasma glucose (in diabetic patients), weight loss, increased exercise, and decreased alcohol consumption.^[335] Other possible preventive measures include dietary antioxidants, low-dose aspirin, and a decrease of intake of saturated fatty acids.^[335] Until very recently, there was felt to be substantial evidence that administration of hormone replacement therapy in postmenopausal women was associated with a reduced risk of stroke.^{[335] [363]} Such therapy often included other compounds that have estrogen-like effects.^[364] Recent findings that demonstrate that administration of estrogen to postmenopausal women may lead to an increased risk of breast cancer and thrombotic episodes has served to decrease the routine administration of such agents.^[365] However, there are new drugs that are in the final stages of testing that have many of the beneficial effects of estrogens and less of the objectionable side effects.^[364] Although management of hypertension is known to decrease the incidence of stroke, not all antihypertensive agents are of equal efficacy. In general, only beta-blockers, thiazide diuretics, and angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce the incidence of stroke, whereas alpha-adrenergic blocking agents and calcium channel blockers may not.^{[366] [367]} Data is not yet available as to whether the angiotensin receptor blocking agents (ARBs) will also decrease the incidence of stroke,^[368] although the data is promising.^[369]

TABLE 51-9 -- Strategies for Prevention of Stroke

Cessation of smoking

Daily exercise

Healthy diet (low fat, modest protein, high fiber)

Management and control of hypertension

Control of diabetes

Control of cholesterol, triglyceride and homocysteine

Management of atrial fibrillation

Weight control

Management of Stroke

The management of acute stroke has lagged far behind that for myocardial infarction. Aside from supportive therapy, specific treatments are poorly developed and are insufficiently utilized. Given that the aforementioned are likely mechanisms of brain damage in stroke, a whole new field is opened as far as potential therapeutic agents for decreasing brain damage associated with stroke. Such agents include calcium channel blockers,^{[370] [371]} inhibitors of NMDA receptors,^[372] and agents that scavenge free radicals.^[373] Other more clinical therapies include thrombolysis, hyperbaric oxygen, and antiplatelet agents.^{[345] [346] [347]} It is now clear that in many cases acute stroke can often be successfully treated, but only if physicians realize that stroke should now be considered a medical emergency where timely therapy can make the difference in functional survival of the brain. Therapies for acute stroke that are now being administered in teaching hospitals in the United States start with acute neuroimaging in the emergency room. An initial CT scan will usually reveal acute stroke and if present, serves to differentiate occlusive from hemorrhagic stroke. If a non-hemorrhagic stroke is present, treatment prospects can be examined with magnetic resonance angiography (MRA), which is non-invasive. Contrast should not be administered to patients with impaired renal function, but can be given to dialysis patients.^[374] When acute stroke is diagnosed within the appropriate time window (within 3 hours of the onset of symptoms) current therapies may include intravenous thrombolytic therapy,^[375] intraarterial thrombolytic therapy, antithrombotic and antiplatelet drugs, defibrinogenating agents, and neuroprotective drugs.^{[355] [376] [377] [378]} Administration of the defibrinogenating agent ancrod to patients with acute ischemic stroke resulted in a better functional status after 3 months follow-up.^[378] Nizofenone can scavenge free radicals and inhibit glutamate release, and may prove useful as a cerebroprotective agent.^{[355] [379]} Some cases of acute stroke will be due to dissection of the carotid or vertebral artery systems. These patients have lesions that are not amenable to dissolution of clot, as the obstructing lesions is in fact a hemorrhage in the arterial wall.^{[380] [381]}Dissection of the carotid or vertebral artery system can be initiated by chiropractic manipulation of the cervical spine, so that such maneuvers should probably be avoided in dialysis patients. In addition, some cases of apparent acute stroke in dialysis patients will be due to subdural hematoma, which must always be considered in the differential diagnosis of stroke in dialysis patients. Another potential cause of stroke is the use of over-the-counter medications (dietary supplements) containing ephedra (phenylpropanolamine).^[325] Although recent publicity relates to the death of athletes that may have been associated with the use of ephedra-containing products,^[382] there have been multiple reports of stroke in ordinary individuals after use of such agents, often for weight control.^[383]

Angioplasty of cerebral vessels in patients with acute stroke is uncommon and data concerning its efficacy is scarce. For carotid insufficiency, data is available on the effects of stent placement.^[344] The use of hyperbaric oxygen therapy in patients with acute stroke has thus far not demonstrated any improvement.^[345] Antiplatelet therapy has been widely used for the prevention of secondary stroke, particularly in patients who have suffered a transient ischemic attack (TIA). The main drugs utilized are aspirin, dipyridamole, and clopidogrel.^[346] All have some efficacy, but unfortunately, both aspirin and clopidogrel are often complicated by bleeding problems, especially when used in combination. Data is accumulating and the indications are still not resolved. The use of thrombolysis (tissue plasminogen activator) in patients with acute stroke has been extensively studied in patients with myocardial infarction. However, the use of tissue plasminogen activator in patients with acute stroke is highly controversial, with the indications not at all clear.^[347] Following the use of thrombolysis in acute stroke, arterial recanalization is augmented by continuous transcranial Doppler.^[348] It does appear that in patients who have had an ischemic stroke, the risk of a subsequent stroke or myocardial infarction is substantially increased.^[349] Ischemic leading to stroke only initiates biochemical events that may ultimately lead to brain damage. There exist interventions that can counter these biochemical events. Such interventions should theoretically decrease the brain damage associated with acute stroke, but actual data in this regard is unfortunately lacking at this time.^{[146] [350]}

SEXUAL DYSFUNCTION IN UREMIA

Pathogenesis of Uremic Sexual Dysfunction

Disturbances in sexual function are a common complication of chronic renal failure.^{[12] [128] [384]} These complications include erectile dysfunction, decreased libido, and decreased frequency of intercourse.^{[129] [385]} Studies in uremic rats showed that erectile impairment was associated with a disturbance in nitric oxide synthetase gene expression.^[128] Sexual dysfunction in men with ESRD treated with maintenance hemodialysis is common, and previously, impotence was observed in at least 50% of such patients.^[130] Among patients being treated with chronic hemodialysis, the current incidence of erectile dysfunction is 71% to 82%.^[131] A number of abnormalities associated with renal failure appear to be important in the genesis of impotence (erectile dysfunction). There are abnormalities in autonomic nervous system function,^[385] impairment in arterial and venous systems of the penis (along with vascular pathology in other vascular beds), hypertension (many drugs used to manage hypertension cause secondary impotence), and other associated endocrine abnormalities.^[386] Failure to treat patients with angiotensin-converting inhibitors was an important factor in the development of erectile dysfunction.^[129] There are also the associated effects of aging, with impotence observed in over 50% of men over 60 years old who do not have renal failure.^[387] Erectile dysfunction is also observed in renal allograft recipients.^[388]

Sexual dysfunction is also common in women who are being treated with dialysis.^[132] It is associated with increasing age, dyslipidemia, and depression.^[133] In a comparison of woman on hemodialysis versus controls, dialysis patients had significantly poorer quality of sexual intercourse, less desire, less lubrication, and decreased ability to achieve orgasm.^[133]

Therapy of Sexual Dysfunction in Uremia

There are a variety of approaches to the evaluation of impotency in uremic men.^[389] Patients with ESRD have a high incidence of cardiovascular disease,^[16] which impairs penile vessels along with those of the rest of the body.^[330]The incidence of hypertension is also higher in ESRD patients than the rest of the population, and hypertension is a major contributor to vascular disease.^{[16] [330]} Many drugs used to manage hypertension can lead to impotence (calcium channel blockers, thiazides, guanethidine). The incidence of depression is high in patients with ESRD, and many drugs used to manage depression can lead to impotence (phenothiazine, tricyclics, fluoxetine). Although appreciation of the aforementioned abnormalities may increase our understanding, until very recently, there was little that could be done other than to discontinue certain drugs used to manage hypertension or depression.^[130] There are now a number of drugs that can successfully treat impotence in hemodialysis patients.^[390] Alprostadil was successful, but had to be delivered transurethrally.^[391] In particular, sildenafil can be administered orally and is highly effective, even in men who have cardiovascular disease^[392] or uremia.^{[393] [394]} Other treatments for impotence among men with ESRD include penile prostheses, direct injection of alpha blocking agents or other vasodilators (papaverine, phentolamine, alprostadil) into the penis, and vacuum constrictive devices.^{[384] [390]} In general, sildenafil is very effective for the management of erectile dysfunction in dialysis patients with ESRD, with 81% of such patients showing improvement.^[388] Other competing drugs, such as vardenafil and tadalafil, work by a similar mechanism as does sildenafil, and thus should be effective in patients with ESRD. However, efficacy in patients with ESRD has not yet been established for vardenafil and tadalafil. There is much less work on the management of sexual dysfunction in women. More than 50% of the women studied had no sexual activity.^[133]

UREMIC NEUROPATHY

Clinical Manifestations

Peripheral neuropathy in patients with renal failure has been recognized for over 100 years.^[395] This disorder, however, was not fully appreciated until the early 1960s.^[221] Prior to the institution of chronic dialysis therapy, approximately 65% of patients with end-stage renal disease probably did not live long enough to develop clinically apparent neuropathy. Although existing data are difficult to evaluate, neuropathy is probably present in about 65% of patients with end-stage renal disease at the time of the institution of dialysis.^[396]

Many patients with chronic renal failure who are neurologically asymptomatic may exhibit abnormalities on physical examination. They may also have evidence of autonomic neuropathy such as impotence and postural hypotension. Moreover, in patients who have renal insufficiency, abnormal nerve conduction may be present in the absence of symptoms or abnormal findings on physical examination. Additionally, alternations in nerve conduction do not necessarily indicate structural changes in the peripheral nerves. It is often overlooked that many patients with ESRD have autonomic dysfunction, which in turn results in impaired baroreceptor sensitivity, which can impair blood pressure regulation.^[397]

The motor nerve conduction velocity (MNCV) is a test that is frequently used to assess peripheral neuropathy. The test, however, is somewhat unreliable because there is a large normal variation in MNCV (up to 20% on a day-to-day basis)^[214] and the test has very limited utility in detecting moderate impairment of peripheral nerve function. Sensory nerve conduction velocity (SNCV) is more sensitive than MNCV, but the test is quite painful and most patients do not permit repeated tests.

In general, there are two broad categories of peripheral neuropathy. These are described in terms of the pattern of involvement of the peripheral nervous system. First, there are processes that result in a bilaterally symmetric disturbance of function that can be designated as polyneuropathies. Polyneuropathy tends to be associated with agents such as toxic substances, metabolic disorders (uremia, diabetes, deficiency states), and certain examples of immune reaction that act diffusely on the peripheral nervous system. The second category comprises isolated lesions of peripheral nerves (mononeuropathy) or multiple isolated lesions (multiple mononeuropathy). In severe symmetric polyneuropathies, a generalized loss of peripheral nerve function may occur, and the impairment is usually maximal distally in the limbs. A mixed motor and sensory polyneuropathy with a distal distribution results in weakness and wasting that is most frequently observed peripherally in the arms and legs. There are also distal sensory changes of “glove and stocking” distribution. In those neuropathies that involve “dying back” of the axons from the periphery,^[395] it is possible that the neurons that have the longest axons to maintain appear to be the first to suffer.

Uremic neuropathy is a distal, symmetric, mixed polyneuropathy. Motor and sensory modalities are both generally affected and lower extremities are more severely involved than are the upper extremities. Clinically, uremic polyneuropathy cannot be distinguished from the neuropathies associated with certain other metabolic disorders such as diabetes mellitus, chronic alcoholism, and various deficiency states. The occurrence of neuropathy bears no relationship to the type of underlying disease process (i.e., glomerulonephritis or pyelonephritis). However, certain diseases that can lead to renal failure may simultaneously affect peripheral nerve function in a manner separate from the manifestations of uremia. Such diseases include amyloidosis, multiple myeloma, systemic lupus erythematosus, polyarteritis, nodosa, diabetes mellitus, and hepatic failure.^[221] The clinical manifestations of uremic neuropathy are characterized by several different stages. It appears that when glomerular filtration rate exceeds 12 ml per minute, clinical evidence of neuropathy is generally absent.

Peripheral Nerves

The restless leg syndrome is a common early manifestation of chronic renal failure. Clinically, patients experience sensations in lower extremities such as crawling, prickling, and pruritus. The sensations are worse distally than proximally and are generally more prominent in the evening. The restless leg syndrome may initially be present in up to 40% of patients with chronic renal failure.^[398] Another symptom experienced by patients with early uremic neuropathy is the burning foot syndrome, which is present in less than 10% of patients with chronic renal failure.^[399] Rather than “burning,” the actual symptoms consist of swelling sensations, constriction, and tenderness of the distal lower extremities.

The physical signs of peripheral nerve dysfunction often begin with loss of deep tendon reflexes, particularly knee and ankle jerks.^{[316] [317]} Impaired vibratory sensation is also an early sign of uremic neuropathy. Loss of sensation in the lower leg is common and often takes the form of “stocking glove” anesthesia of the lower leg. The sensory loss includes pain, light touch, vibration, and pressure.

Metabolic Neuropathy

Uremic neuropathy is one of a group of central-peripheral axonopathies, also known as dying-back polyneuropathies, which have been described by Spencer and Schaumberg.^[400] The causes of such central-peripheral axonopathies include many types of toxic compounds. These include neuropathies associated with diabetes, multiple myeloma, certain hereditary polyneuropathies, and uremia.^[400] The causes of such central-peripheral axonopathies include many types of toxic compounds.^[400] These include neuropathies associated with diabetes, multiple myeloma, amyloidosis, certain hereditary polyneuropathies, and uremia.^[400] There is also an associated degeneration of the spinal cord, particularly involving posterior columns, as well as other portions of the central nervous system. Such findings are usually attributed either to local central nervous system disease or to damage of spinal ganglion cells secondary to ascending peripheral nervous system damage. It is likely, however, that the central nervous system components of distal axonopathies. The clinical characteristics of such distal axonopathies as described by Schaumberg and Spencer include the following^[400]:

	1.	Insidious onset. In most human toxic neuropathies, there is a steady low-level exposure. Because only the distal portion of selected, scattered fibers are affected, the patient may still function well despite the axonal degeneration.
	2.	Onset in legs. Large and long axons are affected early, and fibers of the sciatic nerve are especially vulnerable.
	3.	Stocking-glove sensory loss. Degeneration in the distal axon proceeds toward the cell body, resulting in clinical signs in the feet and hands initially.
	4.	Early loss of Achilles reflex. Fibers to the calf muscles are of large diameter and among the first affected by many toxins, even when longer, smaller-diameter axons in the feet are spared.
	5.	Moderate slowing of motor nerve conduction. In demyelinating neuropathies, motor nerves or roots are diffusely affected; in axonal neuropathies, scattered motor fibers are often intact and motor nerve conduction velocity may appear normal or only slightly slow despite severe paresis.
	6.	Normal cerebrospinal fluid protein content. Pathologic changes are usually distal and nerve roots are spared.
	7.	Slow recovery. Axonal regeneration (in contrast to remyelination) is slow—about 1 mm per day. Thus, after institution of dialysis or renal transplantation, recovery of nerve function may take months or years.
	8.	Residual disability. Most toxic axonopathies are characterized by tract degeneration of long, large-diameter fibers in the central nervous system concomitant with changes in the peripheral nervous system. Signs of lesions in the corticospinal and spinocerebellar pathways may not be clinically apparent if there is severe peripheral neuropathy. However, on recovery from the neuropathy, there may be spasticity or ataxia.

It can readily be recognized that these features are similar to many descriptions of uremic neuropathy.^{[221] [395] [401]} The cellular basis for distal axonopathies, however, remains unclear. Spencer and associates^[402] have emphasized that a number of chemically unrelated neurotoxic compounds and several types of metabolic abnormalities can cause strikingly similar patterns of distal symmetric polyneuropathy in humans and animals.

These authors suggest a possible common metabolic basis for many distal axonopathies. Neurotoxic compounds may deplete energy supplies in the axon by inhibiting nerve fiber enzymes required for the maintenance of energy synthesis. Resupply of enzymes from the neuronal soma may fail to meet the increased demand for enzyme replacement in the axon, causing the concentration of enzymes to decrease in distal regions. This could lead to a local blockade of energy-dependent axonal transport, which could then produce a series of pathologic changes culminating distal nerve fiber degeneration. Among uremic patients who also have diabetes mellitus, oxidative stress, including superoxide accumulation, and accumulation of advanced glycation end products (AGEs) appear to be major contributors to the development of uremic neuropathy.^{[3] [8] [152]} In experimental diabetic neuropathy, there was a significant reduction in desert hedgehog mRNA,^[403] which was substantially improved by treatment with sonic hedgehog-IgG fusion protein.^[403] Such an approach may be promising in the management of uremic neuropathy as well.

In addition to uremic neuropathy, uremic myopathy is a frequent cause of weakness, exercise limitation, and rapid onset tiredness in dialysis patients.^{[120] [404]} Later on, muscle wasting occurs, particularly in the limb muscles.

Uremic Toxins and Nerve Conduction

Several possible uremic toxins have been identified that appear to be correlated with depression of MNCV in laboratory animals.^{[197] [212] [213]} However, these studies do not take into account the fact that (1) depressed MNCV is cyclical, with abnormal low values one day and normal values the next, (2) there is a day-to-day variation in MNCV that approaches 20%,^[214] (3) the finding of depressed MNCV in laboratory animals associated with high plasma levels of potential uremic neurotoxins has generally not been confirmed in human subjects with renal failure.^[65] Although it is possible to relate impairment in MNCV with levels in blood of various substances, the best correlation was obtained between reduced MNCV versus a reduction in glomerular filtration rate (see Table 51-4 ).

Parathyroid Hormone

Among the potential uremic neurotoxins is parathyroid hormone.^[69] This supposition ignores the criteria suggested by Bergstrom and Furst,^[193] and is based instead on a possible correlation between plasma parathyroid hormone levels and MNCV in patients with chronic renal failure.^[215] Some earlier studies suggested a possible effect of parathyroid hormone on MNCV in the dog^[213] but these early impressions have not been confirmed.^{[53] [219]} In fact, if the early data in humans are critically examined, the correlation coefficient (r value) when MNCV is graphed versus parathyroid hormone level is -0.45.^[215] This means that r^[2] = 0.202, and 1 - r^[2] = 0.8. Thus, for any change in MNCV, 80% could not be due to an effect of parathyroid hormone. Thus, the original data is substantially flawed, even further weakening the argument for an implied relationship between parathyroid hormone and impaired nerve function in uremia. In patients who have hyperparathyroidism, without uremia, parathyroid hormone has no observable effect on peripheral nerve function.^{[53] [218] [219]} In both patients and laboratory animals with acute renal failure, the MNCV has been found to be normal.^{[24] [65] [191] [220]} In all studies of both patients and laboratory animals with chronic renal failure, the MNCV has not been shown to be affected by parathyroid hormone.^[65] Thus, in both patients and laboratory animals with either acute renal failure or chronic renal failure, or primary or secondary hyperparathyroidism, no effect of parathyroid hormone on nerve function can be demonstrated. In patients with chronic renal failure, there is no change in MNCV as a result of either recovery of renal function or chronic hemodialysis; there was also no effect of parathyroidectomy.^[219] In addition, when patients begin dialysis therapy, MNCV either stabilizes or improves.^[221] However, virtually all of these patients have elevated plasma parathyroid hormone levels.^[222]

Animal studies suggest that in either acute renal failure or chronic renal failure, changes in MNCV take longer than 6 months to develop and are probably not related to an effect of parathyroid hormone.^[53] Mahoney and associates studied dogs who had renal failure for periods of 3.5 days to 6 months.^[79] There was no change in the MNCV after any of the aforementioned intervals of renal failure, and the MNCV was normal even after 6 months with glomerular filtration rate below 22% of control.

It has also been suggested, without adequate explanation and without confirmation, that either parathyroid hormone or acute renal failure resulted in an increase of nerve calcium content and that this might be related to impaired MNCV.^[213] This postulate must now be considered as both unlikely and unproven. In dogs with renal failure for periods of 3.5 days to 4 months, there were no observed increases in nerve calcium content.^[79] Nerve calcium values in dogs with acute renal failure with or without parathyroidectomy also were not different and in fact actually fell significantly (versus control) in dogs with chronic renal failure.

Acknowledgment

The research in this manuscript was supported by a grant from the National Institutes of Health (NIH), National Institute of Aging, Grant # AG-08575-02S1. The support of Doctors Charles Kleeman, Cosmo Fraser, F. Kanda, Z. Vexler, Raul Guisado, Cynthia Mahoney, and Jerry Cooper, and Technicians Virginia Lazarowitz, Phillip Sarnacki, Will Leach, and Alice Kerian is gratefully acknowledged. I wish to thank my wife Patricia N. Hale, JD, for her inspirational and intellectual support and assistance.

References

1. Stone WJ: Beta 2 -microglobulin-associated amyloidosis of end-stage renal disease. In: Henrich WL, ed. Principles and Practice of Dialysis, Baltimore: Williams & Wilkins; 1994:225-233.

2. Takayama F, Miyazaki S, Morita T, et al: Dialysis related amyloidosis of the heart in long-term hemodialysis patients. Kidney Int 2002; 59(suppl 78):S172-S176.

3. Feldman E: Oxidative stress and diabetic neuropathy: A new understanding of an old problem. J Clin Invest 2003; 111:431-433.

4. Kennedy R, Case C, Fathi R, et al: Does renal failure cause an atherosclerotic milieu in patients with end-stage renal disease?. Am J Med 2001; 110:198-204.

5. Hsu C, McCulloch CE, Curhan GC: Epidemiology of anemia associated with chronic renal insufficiency among adults in the United States: Results from the Third Health and Nutrition Examination Survey. J Am Soc Nephrol 2002; 13:504-510.

6. Levin A: Anemia and left ventricular hypertrophy in chronic kidney disease populations. Kidney Int 2002; 61(suppl 80):S35-S38.

7. Himmelfarb J, Stenvinkel P, Ikizler TA, Hakim RM: The elephant in uremia: Oxidative stress as a unifying concept of cardiovascular disease in uremia. Kidney Int 2002; 62:1524-1538.

8. Miyata T, Sugiyama S, Saito A, Kirokawa K: Reactive carbonyl compounds related uremic toxicity (carbonyl stress). Kidney Int 2001; 59(suppl 78):S25-S31.

9. Vanholder R, De Smet R, Lameire N: Protein-bound uremic solutes: The forgotten toxins. Kidney Int 2001; 59(suppl 78):S266-S270.

10. Pereira AA, Weiner DE, Scott T, et al: Cognitive function in dialysis patients. Am J Kidney Dis 2005; 45:448-462.

11. Arieff AI: Neurological complications of renal insufficiency. In: Brenner BM, ed. Brenner & Rector's The Kidney, 7th ed. Philadelphia: WB Saunders; 2004:2227-2254.

12. Palmer BF: Sexual dysfunction in uremia. J Am Soc Nephrol 1999; 10:1381-1388.

13. Iseki K, Fukiyama K: Predictors of stroke in patients receiving chronic hemodialysis. Kidney Int 1996; 50:1672-1675.

14. Seliger SL, Gillen DL, Longstreth WT, Kestenbaum B: Risk of stroke among patients with end-stage renal disease. Kidney Int 2003; 64:603-609.

15. Martinez-Vea A, Salvado E, Bardaji A, et al: Silent cerebral white matter lesions and their relationship with vascular risk factors in middle-aged predialysis patients with CKD. Am J Kidney Dis 2006; 47:241-250.

16. Meeus F, Kourilsky O, Guerin AP, et al: Pathophysiology of cardiovascular disease in hemodialysis patients. Kidney Int 2000; 58(suppl 76):S140-S147.

17. Stenvinkel P, Pecoits-Filho R, Lindholm B: Coronary artery diease in end-stage renal disease: No longer a simple plumbing problem. J Am Soc Nephrol 2003; 14:1927-1939.

18. Go AS, Chertow GS, Fan D, et al: Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351:1296-1305.

19. Wratten ML, Tetta C, Ursini F, Sevanian A: Oxidant stress in hemodialysis: Prevention and treatment strategies. Kidney Int 2000; 58(suppl 76):S126-S132.

20. Slomowitz LA, Wilkinson A, Hawkins R, Danovitch G: Evaluation of kidney function in renal transplant patients receiving long-term cyclosporine. Am J Kidney Dis 1990; 15(6):530-534.

21. Chan L, Wang W, Kam I: Outcomes and complications of renal transplantation. In: Schrier RW, Gottschalk CW, ed. Diseases of the Kidney, 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2001:2871-2938.

22. Murray AM, Tupper DE, Knopman DS, et al: Cognitive impairment in hemodialysis patients is common. Neurol 2006; 67:216-223.

23. Locke SJ, Merrill JP, Tyler HR: Neurological complications of acute uremia. Arch Intern Med 1961; 108:519-530.

24. Cooper JD, Lazarowitz VC, Arieff AI: Neurodiagnostic abnormalities in patients with acute renal failure. Evidence for neurotoxicity of parathyroid hormone. J Clin Invest 1978; 61:1448-1455.

25. Fraser CL, Arieff AI: Nervous system manifestations of renal failure. In: Schrier RW, Gottschalk CW, ed. Diseases of the Kidney, 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2001:2769-2794.

26. Moe SM, Sprague SM: Uremic encephalopathy. Clin Nephrol 1994; 42:251-256.

27. Data System USR: Excerpts from the USRDS 2005 Annual Data Report: Incidence & Prevalence. Am J Kidney Dis 2005; 47(suppl 1):S17-S32.

28. Data System USR: 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. In: NIH N, ed. US Renal Data System, Bethesda: NIH; 2005.

29. Garg PP, Frick KD, Diener-West M, Powe NR: Effect of the ownership of dialysis facilities on patients' survival and referral for transplantation. N Engl J Med 1999; 341:1653-1660.

30. Goodkin DA, Gragg-Gresham JL, Koenig KG, et al: Association of comorbid conditions and mortality in hemodialysis patients in Europe, Japan, and the United States: The dialysis outcomes and practice patterns study (DOPPS). J Am Soc Nephrol 2003; 14:3270-3277.

31. Pambianco G, Costacou T, Ellis D, et al: The 30-year natural history of type 1 diabetes complications. Diabetes 2006; 55:1463-1469.

32. Depner TA: Dialysis therapy: Role of dialyzer membranes. In: Massry SG, Glassock RJ, ed. Massry and Glassock's Textbook of Nephrology, 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2001:1512-1515.

33. Levin A, Rocco II M: Clinical practice recommendations for hemodialysis adequacy: Guiline 5: Dialyzer membranes and reuse. Am J Kidney Dis 2006; 48(suppl 1):S63-S67.

34. Port FK, Wolfe RA, Hulbert-Shearon TE: Mortality risk by hemodialyzer reuse practice and dialyzer membrane characteristics: Results for the USRDS dialyzer morbidity and mortality study. Am J Kidney Dis 2001; 37:276-286.

35. Miles AM, Friedman EA: Center and home chronic hemodialysis: Outcome and complications. In: Schrier RW, Gottschalk CW, ed. Diseases of the Kidney, 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2001:2807-2838.

36. Jones CA, Krolewski AS, Rogus JJ, et al: Epidemic of end-stage renal disease in people with diabetes in the United States population: Do we know the cause?. Kidney Int 2005; 67:1684-1691.

37. Dirks JH, Robinson S, Burdmann E, et al: Prevention strategies for chronic disease in Latin America. Nature Clin Pract Nephrol 2006; 2:347.

38. Waki K: Impact of diabetes mellitus on transplantation. Clin Transpl 2004; 1:357-377.

39. Arieff AI: Neurologic aspects of endocrine disturbances. In: Joynt RJ, Griggs RC, ed. Baker and Joynt's Clinical Neurology, Philadelphia: Lippincott Williams & Wilkins; 2004:CD-ROM.

40. Griggs RC, Satran R: Metabolic encephalopathy. In: Rosenberg RN, Grossman RG, ed. Neurology/Neurosurgery, New York: Churchill-Livingstone; 1983:651-653.

41. Adams RD, Victor M: The acquired metabolic disorders of the nervous system: Hypoxic-hypotensive encephalopathy. In: Adams RD, Victor M, ed. Principles of Neurology, 3rd ed. New York, NY: McGraw-Hill; 1985:788-791.

42. Teschan PE, Bourne JR, Reed RB: Electrophysiological and neurobehavioral responses to therapy: The National Cooperative Dialysis Study. Kidney Int 1983; 23:558.

43. Hirakata H, Yao H, Osato S, et al: CBF and oxygen metabolism in hemodialysis patients: Effects of anemia correction with recombinant human EPO. Am J Physiol 1992; 262:F737-F743.(Renal Fluid Electrolyte Physiol 31)

44. Ifudu O, Feldman J, Friedman EA: The intensity of hemodialysis and the response to erythropoietin in patients with end-stage renal disease. N Engl J Med 1996; 334:420-425.

45. Nissenson AR: Epoetin and cognitive function. Am J Kidney Dis 1992; 20:21-24.

46. Kokot F, Wiecek A: Evidence that the anemia of renal failure participates in overall uremic toxicity. Kidney Int 1997; 52(suppl 62):S83-S86.

47. Grimm G, Stockenhuber F, Schneeweiss B, et al: Improvement of brain fuunction in hemodialysis patients treated with erythropoietin. Kidney Int 1990; 38:480-486.

48. Moreno F, Sanz-Guajardo D, Lopez-Gomez J, et al: Increasing the hematocrit has a beneficial effect on quality of life and is safe in selected hemodialysis patients. J Am Soc Nephrol 2000; 11:335-342.

49. Ayus JC, Go AS, Valderrabano F, et al: Effects of erythropoietin on left ventricular hypertrophy in adults with severe chronic renal failure and hemoglobin <10 g/dl. Kidney Int 2005; 68:788-795.

50. Jeren-Strujic B, Raos V, Jeren T, Horvaitin-Godler S: Morphologic and functional changes of left ventricle in dialyzed patients after treatment with recombinant human erythropoietin. Angiology 2000; 2000:131-139.

51. Narula J, Haider N, Virmani R: Apoptosis in myocytes in end-stage heart failure. N Engl J Med 1996; 335:1182-1189.

52. Cogan MG, Covey C, Arieff AI, et al: Central nervous system manifestations of hyperparathyroidism. Am J Med 1978; 65:963-970.

53. Mahoney CA, Arieff AI, Leach WJ, Lazarowitz VC: Central and peripheral nervous system effects of chronic renal failure. Kidney Int 1983; 24(2):170-177.

54. Guisado R, Arieff AI, Massry SG, et al: Changes in the electroencephalogram in acute uremia. Effects of parathyroid hormone and brain electrolytes. J Clin Invest 1975; 55(4):738-745.

55. Crammer JL: Calcium metabolism and mental disorder. Psychol Med 1977; 7:557.

56. Gatewood JW, Organ CH, Mead BT: Mental changes associated with hyperparathyroidism. Psychiatry 1975; 123:129.

57. Heath H, Hodgson SF, Kennedy MA: Primary hyperparathyroidism: Incidence, morbidity, and potential impact in a community hospital. N Engl J Med 1980; 302:189-193.

58. Luxenberg J, Feigenbaum LZ, Aron JM: Reversible long-standing dementia with normocalcemic hyperparathyroidism. J Am Geriatr Soc 1984; 32:546-547.

59. Fraser CL, Arieff AI: Hepatic encephalopathy. N Engl J Med 1985; 313(14):865-873.

60. Ong JP, Aggarwal A, Kriegr D, et al: Correlation between ammonia levels and the severity of hepatic encephalopathy. Am J Med 2003; 114:188-193.

61. Kuhns M, Medina M, McNamara A: Detection of hepatitis C virus RNA in hemodialysis patients. J Am Soc Nephrol 1994; 4:1491-1496.

62. Takabatake T, Ohta H, Ishida Y, et al: Low serum creatinine levels in severe hepatic disease. Arch Intern Med 1988; 148:1313-1315.

63. Papadakis MA, Arieff AI: Unpredictability of clinical evaluation of renal function in cirrhosis. Am J Med 1987; 82(5):945-952.

64. Gines P, Jimenez W: Aquaretic agents: A new potential treatment of dilutional hyponatremia in cirrhosis. J Hepatol 1996; 24:506-512.

65. Pereira AA, Weiner DE, Scott T, et al: Subcortical cognitive impairment in dialysis patients. Hemodial Int 2007; 11:309-314.

66. Levin A, Rocco M: Clinical practive guidelines for hemodialysis adequacy. Am J Kidney Dis 2006; 48(suppl 1):S13-S158.

67. Kiley JE, Woodruff MW, Pratt KI: Evaluation of encephalopathy by EEG frequency analysis in chronic dialysis patients. Clin Nephrol 1976; 5:245-250.

68. Basile C, Miller JD, Koles ZJ, Grace M: The effects on brain water and EEG in stable chronic uremia. Am J Kidney Dis 1987; 9:462-469.

69. Slatopolsky E, Martin K, Hruska K: Parathyroid hormone metabolism and its potential as a uremic toxin. Am J Physiol 1980; 239:F1-F12.(Renal Fluid Electrolyte Physiol. 8)

70. Bowling PS, Bourn JR: Discriminant analysis of electroencephalograms recorded from renal patients. IEEE Trans Biomed Eng 1978; 25:12.

71. Mahoney CA, Arieff AI: Uremic encephalopathies: Clinical, biochemical and experimental features. Am J Kidney Dis 1982; 2(3):324-336.

72. Fraser CL, Arieff AI: Metabolic encephalopathy as a complication of acid base, and electrolyte disorders. In: Arieff AI, DeFronzo RA, ed. Fluid, Electrolyte and Acid-Base Disorders, 2nd ed. New York: Churchill Livingstone; 1995:685-740.

73. Teschan PE: A prospective study of reduced dialysis. ASAIO J 1983; 6:108.

74. Fraser CL, Arieff AI: Metabolic encephalopathy as a complication of renal failure: Mechanisms and mediators. In: Matuschak GM, ed. New Horizons: The Science and Practice of Acute Medicine, 5th ed. Baltimore: Williams & Wilkins; 1994:518-526.

75. Osberg JW, Meares GJ, McKee DC, Burnett GB: Intellectual functioning in renal failure and chronic dialysis. J Chronic Dis 1982; 35:445-457.

76. English A, Savage RD, Britton PG, et al: Intellectual impairment in chronic renal failure. Br Med J 1978; 1:888-890.

77. Greenberg MD: Brain damage in hemodialysis patients. Dialy Transplant 1978; 7:238.

78. Minkoff L, Gaertner M, Darah C, et al: Inhibition of brain sodium-potassium ATPase in uremic rats. J Lab Clin Med 1972; 80:71-78.

79. Mahoney CA, Sarnacki P, Arieff AI: Uremic encephalopathy: Role of brain energy metabolism. Am J Physiol 1984; 247:F527-F532.(Renal Fluid Electrolyte Physiol 16)

80. Van den Noort S, Eckel RE, Brine K, Hrdlicka JT: Brain metabolism in uremic and adenosine-infused rats. J Clin Invest 1968; 47:2133-2142.

81. Arieff AI, Massry SG, Barrientos A, Kleeman CR: Brain water and electrolyte metabolism in uremia: Effects of slow and rapid hemodialysis. Kidney Int 1973; 4:177-187.

82. Arieff AI, Massry SG: Calcium metabolism of brain in acute renal failure. Effects of uremia, hemodialysis, and parathyroid hormone. J Clin Invest 1974; 53(2):387-392.

83. Arieff AI, Guisado R, Massry SG: Central nervous system pH in uremia and the effects of hemodialysis. J Clin Invest 1977; 58:306.

84. Perry TL, Yong VW, Kish SJ, et al: Neurochemical abnormalities in brain of renal failure patients treated by repeated hemodialysis. J Neurochem 1985; 45(4):1043-1048.

85. Fishman RA: Permeability changes in experimental uremic encephalopathy. Arch Int Med 1970; 126:835-837.

86. Verkman AS, Fraser CL: Water and non-electrolyte permeability in brain synaptosomes isolated from normal and uremic rats. Am J Physiol 1986; 250:R306-R312.(Regulatory Integrative Comp Physiol 19)

87. Deferrari G: Brain metabolism of amino acids and ammonia in patients with chronic renal insufficiency. Kidney Int 1981; 20:505.

88. Akmal M, Goldstein DA, Multani S, Massry SG: Role of uremia, brain calcium and parathyroid hormone on changes in electroencephalogram in chronic renal failure. Am J Physiol 1984; 246:F575-F579.(Renal Fluid Electrolyte Physiol 15):

89. Arieff AI: Neurological manifestations of uremia. In: Brenner BM, Rector Jr. FC, ed. The Kidney, 3rd ed. Philadelphia: WB Saunders; 1986:1731-1756.

90. Levin GE, Baron DN: Leucocyte intracellular pH in patients with metabolic acidosis or renal failure. Clin Sci (Oxford) 1977; 52:325.

91. Maschio G, Bazzato G, Bertaglia E, et al: Intracellular pH and electrolyte content of skeletal muscle in patients with chronic renal acidosis. Nephron 1970; 7:481-487.

92. Tizianello A, Deferrari G, Gurreri G, Acquarone N: Effects of metabolic alkalosis, metabolic acidosis and uraemia on whole-body intracellular pH in man. Clin Sci Mol Med (Oxford) 1977; 52:125-135.

93. Pauli HG, Vorburger C, Reubi F: Chronic derangements of cerebrospinal fluid acid base components in man. J Appl Physiol 1962; 17:993-998.

94. De Deyn PP, D'Hooge R, Van Bogaert P, Marescau B: Endogenous guanidino compounds as uremic neurotoxins. Kidney Int 2002; 59(suppl 78):S77-S83.

95. De Deyn PP, Marescau B, D'Hodge R, et al: Guanidino compound levels in brain regions of non-dialyzed uremic patients. Neurochem Int 1995; 27:227-237.

96. Fraser CL, Sarnacki P: Parathyroid hormone mediates changes in calcium transport in uremic rat brain synaptosomes. Am J Physiol 1988; 254:F837-F844.(Renal Fluid Electrolyte Physiol (23)

97. Ischiropoulos H, Beckman JS: Oxidative stress and nitration in neurodegeneration: Cause, effect, or association. J Clin Invest 2003; 111:163-169.

98. Fraser CL, Sarnacki P, Arieff AI: Calcium transport abnormality in uremic rat brain synaptosomes. J Clin Invest 1985; 76(5):1789-1795.

99. Fraser CL, Arieff AI: Abnormalities of transport in synaptosomes from uremic rat brain: role of parathyroid hormone. J Gen Physiol 1986; 88:24.

100. Fraser CL, Sarnacki P, Budayr A: Evidence that parathyroid hormone-mediated calcium transport in rat brain synaptosomes is independent of cyclic adenosine monophosphate. J Clin Invest 1988; 81:982-988.

101. Arieff AI, Fraser CL, Rowley H, et al: Metabolic encephalopathy. In: Kucharczyk J, Moseley M, Barkovich AJ, ed. Magnetic Resonance Neuroimaging, 1st ed. Boca Raton, FL: CRC Press; 1994:319-349.

102. Siddiqui JY, Fitz AE, Lawton RL: Causes of death in patients receiving long-term hemodialysis. JAMA 1970; 212:1350.

103. Olsen S: The brain in uremia. Acta Psychiat Scand 1961; 36(suppl. 156):1-128.

104. Chen CL, Lai PH, Chou KJ, et al: A preliminary report of brain edema in patients with uremia at first hemodialysis. Am J Neuroradiol 2007; 28:68-71.

105. De Leeuw FE, de Groot JC, Oudkerk M: Hypertension and cerebral white matter lesions in a prospective cohort study. Brain 2002; 125:765-772.

106. Prins ND, Van Dijk EJ, den Heijer T: Cerebral white matter lesions and the risk of dementia. Arch Neurol 2004; 61:1531-1534.

107. Moe SM, Chertow GM: The case against calcium-based phosphate binders. Clin J Am Soc Nephrol 2006; 1:697-703.

108. Savazzi GM, Cusamo F, Vinci S, Allegri L: Progression of cerebral atrophy in patients on regular hemodialysis treatment: Long-term follow-up with cerebral computed tomography. Nephron 1995; 69:29-33.

109. Savazzi GM: Pathogenesis of cerebral atrophy in uraemia. Nephron 1988; 49:94-103.

110. Papageorgiou C, Ziroyannis P, Vathylakis J: A comparative study of brain atrophy by computerized tomography in chronic renal failure and chronic hemodialysis. Acta Neurol Scand 1982; 66:378-384.

111. Fraser CL, Arieff AI: Neuropsychiatric complications of uremia. In: Brady HR, Wilcox CS, ed. Therapy in Nephrology and Hypertension, Philadelphia: WB Saunders; 1999:488-490.

112. Okada J, Yoshikawa K, Matsuo H, Oouchi M: Reversible MRI and CT findings in uremic encephalopathy. Neuoradiology 1991; 33:524-526.

113. Wang HC, Brown P, Lees AJ: Acute movement disorders with bilateral basal ganglia lesions in uremia. Movement Dis 1998; 13:952-957.

114. Korzets Z, Zeltzer E, Rathaus M, et al: Uremic optic neuropathy. A uremic manifestation mandating dialysis. Am J Nephrol 1998; 18:240-242.

115. Guy J, Johnston PK, Corbett JJ, et al: Treatment of visual loss in pseudotumor cerebri associated with uremia. Neurology 1990; 40:28-32.

116. Heilman KM, Moyer RS, Melendex F, et al: A memory defect in uremic encephalopathy. J Neurol Sci 1975; 26:245-249.

117. Dean S, Allegretti C: 25 years of good health. In: McKenna CA, ed. Patient Line, Lexington, MA: FMC Medical Services; 2003:1-3.

118. Levy NB, Cohen LM: Central and peripheral nervous system in uremia: Psychiatric and psychosocial considerations. In: Massry SG, Glassock RJ, ed. Massry and Glassock's Textbook of Nephrology, 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2001:1279-1282.

119. Bardin T: Musculoskeletal manifestations of chronic renal failure. Curr Opin Rheumatol 2003; 15:48-54.

120. Campistol JM: Uremic myopathy. Kidney Int 2002 2002; 62:1901-1913.

121. Matsumoto N, Ichimura S, Hamaoka T, et al: Impaired muscle oxygen metabolism in uremic children. Am J Kidney Dis 2006; 48:473-480.

122. Lofberg E, Gutierrez A, Anderstam B, et al: Effect of bicarbonate on muscle protein in patients receiving hemodialysis. Am J Kidney Dis 2006; 48:419-429.

123. Eriksen EF, Glerup H: Vitamin D deficiency and aging: Implications for general health and osteoporosis. Biogerontology 2002; 3:73-77.

124. Mosekilde L: Vitamin D and the elderly. Clin Endocrinol (Oxford) 2005; 62:265-281.

125. Prabhala A, Garg R, Dandona P: Severe myopathy associated with vitamin D deficiency in western New York. Arch Intern Med 2000; 160:1199-1203.

126. Block GA, Martin KJ, de Francisco ALM, et al: Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 2004; 350:1516-1525.

127. Wikstrom B: k-Opioid system in uremic pruritus: Multicenter, randomized, double-blind, placebo-controlled clinical studies. J Am Soc Nephrol 2005; 16:3742-3747.

128. Abdel-Gawad M, Huynh H, Brock GB: Experimental chronic renal failure-asociated erectile dysfunction: Molecular alterations in nitric oxide synthetase pathway and IGF-I system. Molecular Urol 1999; 3:117-125.

129. Rosas SE, Joffe M, Franklin E, Strom BL: Prevalence and determinants of erectile dysfunction in hemodialysis patients. Kidney Int 2001; 59:2259-2266.

130. Massry SG, Smogorzewski MJ, Klahr S: Metabolic and endocrine dysfunctions in uremia. In: Schrier RW, Gottschalk CW, ed. Diseases of the Kidney, 6th ed. Boston, MA: Little, Brown & Co.; 1997:2661-2698.

131. Rosas SE, Joffe M, Franklin E: Prevalence and determinants of erectile dysfunction in hemodialysis patients. Kidney Int 2001; 59:2259-2266.

132. Palmer BF: Sexual dysfunction in men and women with chronic kidney disease and end-stage kidney disease. Adv Ren Replace Ther 2003; 10:48-60.

133. Peng YS, Chiang CK, Kao TW, Hung KY: Sexual dysfunction in female hemodialysis patients: A Multicenter Study. Kidney Int 2005; 68:760-765.

134. Raff MC, Barrers BA, Burne JF, et al: Programmed cell death and the control of cell survival. Science 1993; 262:695-700.

135. Steller H: Mechanisms and genes of cellular suicide. Science 1995; 267:1445-1449.

136. Vexler ZS, Roberts TPL, Bollen AW, et al: Transient cerebral ischemia: Association of apoptosis induction with hypoperfusion. J Clin Invest 1997; 99:1453-1459.

137. Pittman RN, Wang S, DiBenedetto AJ, Mills JC: A system for characterizing cellular and molecular events in programmed neuronal cell death. J Neurosci 1993; 13:3669-3680.

138. Linnik MR, Zobrist R, Hatfield M: Evidence supporting a role for programmed cell death in focal cerebral ischemia in rats. Stroke 1993; 24:2002-2008.

139. Tominaga T, Kure S, Narisawa K, Yoshimoto T: Endonuclease activation following ischemic injury in the rat brain. Brain Res 1993; 608:21-26.

140. de la Monte SM: p53- and CD95-associated apoptosis in neurodegenerative diseases. Lab Invest 1998; 78:401-411.

141. Cohen H, Rdnicki M, Horl WH: Uremic toxins modulate the spontaneous apoptotic cell death and essential functions of neutrophils. Kidney Int 2001; 59(suppl 78):S48-S52.

142. Aoyagi K, Shahrzad S, Iida S, Tomida C: Role of nitric oxide in the synthesis of guanidinosuccinic acid, an activator of the N-methyl-D-aspartate receptor. Kidney Int 2001; 59(suppl 78):S93-S96.

143. Coyle JT, Puttfarcken P: Oxidative stress, glutamate and neurodegenerative disorders. Science 1993; 262:689-695.

144. Bonfoco E, Krainc M, Ankarcrona M, et al: Apoptosis and necrosis. Proc Natl Acad Sci 1995; 92:7162-7166.

145. Chen J, Graham P, Chan P, et al: Bcl-2 is expressed in neurons that survive focal ischemia in the rat. Neuroreport 1995; 6:394-398.

146. Lee JM, Grabb MC, Zipfel GJ, Choi DW: Brain tissue responses to ischemia. J Clin Invest 2000; 106:723-731.

147. Honig LS, Rosenberg RN: Apoptosis and neurologic disease. Am J Med 2000; 108:317-330.

148. Barber AJ, Lieth E, Khin SA, Antonetti DA: Neural apoptosis in the retina during experimental and human diabetes. J Clin Invest 1998; 102:783-791.

149. Ashkenazi A, Dixit VM: Death receptors: Signaling and modulation. Science 1998; 281:1305-1308.

150. Yu SP, Yeh Ch, Strasser M, et al: NMDA receptor-mediated K+ efflux and neuronal apoptosis. Science 1999; 284:336-338.

151. Marnett LJ, Riggins JN, West JD: Endogenous generation of reactiveoxidants and electrophiles and their reactions with DNA and protein. J Clin Invest 2003; 111:583-593.

152. Miyata T, Kirokawa K, van Ypersele de Strihou C: Relevance of oxidative and carbonyl stress to long-term uremic complications. Kidney Int 2000; 58(suppl 76):S120-S125.

153. Sebekova K, Blazicek P, Syrova D, Krivosikova Z: Circulating advanced glycation end product levels in rats rapidly increase with acute renal failure. Kidney Int 2001; 59(suppl 78):S48-S62.

154. Schwedler S, Schinzel R, Vaith P, Wanner C: Inflammation and advanced glycation end product levels in uremia: Simple coexistence, potention or causal relationship?. Kidney Int 2001; 59(suppl 78):S32-S36.

155. Asahi K, Ichimori K, Nakaawa H, Izuhara Y: Nitric oxide inhibits the formation of advanced glycation end products. Kidney Int 2000; 58:1780-1787.

156. Devuyst O, van Yperselle de Strihou C: Nitric oxide, advanced glycation end products, and uremia. Kidney Int 2000; 58:1814-1815.

157. Henry RMA, Kostense PJ, Bos G, Dekker JM: Mild renal insufficiency is associated with increased cardiovascular mortality: The Hoorn study. Kidney Int 2002; 62:1402-1407.

158. Loughrey CM, Young IS, Lightbody JH: Oxidative stress in haemodialysis. Q J Med 1994; 87:679-683.

159. Ritz E, Haxsen V: Angiotensin Ii and oxidative stress: An unholy alliance. J Am Soc Nephrol 2003; 14:2985-2987.

160. Stenvinkel P, Wanner C, Metzger T, et al: Inflammation and outcome in end-stage renal failure: Does female gender constitute a survival advantage?. Kidney Int 2002; 62:1791-1798.

161. May RC, Mitch WE: Pathophysiology of uremia. In: Brenner BM, ed. The Kidney, 4th ed. Philadelphia: WB Saunders; 1996:2148-2169.

162. Morena M, Cristol JP, Senecal L, Leray-Moragues H: Oxidative stress in hemodialysis patients: Is NADPH oxidase complex the culprit?. Kidney Int 1961; 61(suppl 80):S109-S114.

163. Lonnemann G: Chronic inflammation in hemodialysis: The role of contaminated dialysate. Blood Purif 2000; 18:214-223.

164. Sela S, Shurtz-Swirski R, Shapiro G, et al: Oxidative stress during hemodialysis: Effect of heparin. Kidney Int 2002; 59(suppl 78):S159-S163.

165. Mydlik M, Derzsiova K, Racz O, Sipulova A: A modified dialyzer with vitamin E and antioxidant defense parameters. Kidney Int 2002; 59(suppl 78):S144-S147.

166. Huang J: Dehydroascorbic acid, a blood-brain barrier transportable form of vitamin C, mediates potent cerebroprotection in experimental stroke. Proc Natl Acad Sci U S A 2001; 98:11720-11724.

167. Ross R: Atherosclerosis—an inflammatory disease. N Engl J Med 1999; 340:115-126.

168. Rifai N, Buring JE, Lee IM, et al: Is C-reactive protein specific for vascular disease in women?. Ann Intern Med 2002; 136:529-533.

169. Kielstein JT, Zoccali C: Asymmetric dimethylarginine: A cardiovascular risk factor and a uremic toxin coming of age?. Am J Kidney Dis 2005; 46:186-202.

170. Ridker PM, Hennekens CH, Buring JE, Rifai N: C-reactive protein and other markers of inflamation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342:836-843.

171. Cook NR, Buring JE, Ridler PM: The effect of including C-reactive protein in cardiovascular risk prediction models for women. Ann Intern Med 2006; 145:21-29.

172. Stuveling EM, Hillege HL, Bakker SJL, Gans ROB: C-reactive protein is associated with renal function abnormalities in a non-diabetic population. Kidney Int 2003; 63:654-661.

173. Jenkins NP, Keevil BG, Hutchinson IV, Brooks NH: Beta-blockers are associated with lower C-reactive protein concentrations in patients with coronary artery disease. Am J Med 2002; 112:269-274.

174. Caglar K, Peng Y, Pupim LB, Flakoll PJ: Inflamatory signals associated with hemodialysis. Kidney Int 2002; 62:1408-1416.

175. Tanne D, Benderly M, Goldbourt U, et al: C-reactive protein as a predictor of incident ischemic stroke among patients with preexisting cardiovascular disease. Stroke 2006; 37:1720-1724.

176. Mezzano D, Pais EO, Aranda E, Panes O: Inflamation, not hyperhomocysteinemia, is related to oxidative stress and hemostatic and endothelial dysfunction in uremia. Kidney Int 2001; 60:1844-1850.

177. Kaysen GA: The microinflamatory state in uremia: Causes and potential consequences. J Am Soc Nephrol 2001; 12:1549-1557.

178. Nassar GM, Fishbane S, Ayus JC: Occult infection of old nonfunctioning arteriovenous grafts: A novel cause of erythropoietin resistance and chronic inflamation in hemodialysis patients. Kidney Int 2002; 61:S49-S54.

179. Nassar GM, Ayus JC: Infectious complications of old nonfunctioning arteriovenous grafts in renal transplant recipients: A case series. Am J Kidney Dis 2002; 40:832-836.

180. Ayus JC, Sheikh-Hamad D: Silent infection in clotted hemodialysis access grafts. J Am Soc Nephrol 1998; 9:1314-1317.

181. Van Guldener C, Stam F, Stehouwer CDA: Homocysteine metabolism in renal failure. Kidney Int 2002; 59(suppl 78):S234-S237.

182. Perna AF, Ingrosso D, Castaldo P, et al: Homocysteine and transmethylations in uremia. Kidney Int 2002; 59(suppl 78):S230-S233.

183. Mallamaci F, Zoccali C, Tripepi G, et al: Hyperhomocysteinemia predicts cardiovascular outcomes in hemodialysis patients. Kidney Int 2002; 61:609-614.

184. Massy ZA, Ceballos I, Chadefaux-Vekemens B, et al: Homocyst(e)ine, oxidative stress, and endothelium function in uremic patients. Kidney Int 2002; 59(suppl 78):S243-S245.

185. Meng W, Tobin JR, Busija DW: Glutamate-induced cerebral vasodilation is mediated by nitric oxide through N-methyl-D-asparate receptors. Stroke 1995; 26:857-863.

186. Lipton SA, Kim WK, Choi YB: Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A 1997; 94:5923-5928.

187. Shik J, Parfrey P: The clinical epidemiology of cardiovascular disease in chronic kidney disease. Curr Opin Nephrol Hypertens 2005; 14:550-557.

188. Drueke T, Khoa TN, Massy ZA, et al: Role of oxidized low-density lipoprotein in the atherisclerosis of uremia. Kidney Int 2002; 59(suppl 78):S114-S119.

189. Vasan RS, Beiser A, D'Augostino RB, et al: Plasma homocysteine and risk for congestive heart failure in adults without prior myocardial infarction. JAMA 2003; 289:1251-1257.

190. Kosiborod M, Smith GL, Radford MJ, et al: The prognostic importance of anemia in patients with heart failure. Am J Med 2003; 114:112-119.

191. Scribner BH, Farrell PC, Milutinovic J: Evolution of the middle molecular hypothesis. Proc 5th Int Congr Nephrol (Mexico) 1972; 5:190.

192. Man NK: An approach to “middle molecules” identification in artificial kidney dialysate, with reference to neuropathy prevention. Trans Am Soc Artif Intern Organs 1973; 19:320.

193. Bergstrom J, Furst P: Uremic toxins. In: Drukker W, Parsons FM, Maher JF, ed. Replacement of Renal Function by Dialysis, Boston: Martinus Nijhoff Publishers; 1983:354-377.

194. Vanholder R: Low molecular weight uremic toxins. In: Ronco C, Bellomo R, ed. Critical Care Nephrology, Hingham, MA: Kluwer Academic Publishers; 1998:855-868.

195. Vanholder R: Pathogenesis of uremic toxicity. In: Ronco C, Bellomo R, ed. Critical Care Nephrology, Hingham, MA: Kluwer Academic Publishers; 1998:845-853.

196. Horl WH: Atherosclerosis and uremic retention solutes. Kidney Int 2004; 66:1719-1731.

197. Giovannetti S, Balestri PL, Barsotti G: Methylguanidine in uremia. Arch Intern Med 1973; 131:709.

198. Faden AI, Demediuk P, Panter SS, Vink R: The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 1989; 244:798-800.

199. Lipton SA, Rosenberg PA: Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 1994; 330:613-622.

200. Beal MF: Mechanisms of excitotoxicity in neurologic disease. FASEB J 1992; 6:3338-3344.

201. Davidoff F: Guanidine derivatives in medicine. N Engl J Med 1973; 289:141-146.

202. Dhondt A, Vanholder R, van Beisen W, Lameire N: The removal of uremic toxins. Kidney Int 2000; 58(suppl. 76):S47-S59.

203. Scribner BH, Babb AL: Evidence for toxins of “middle” molecular weight. Kidney Int 1975; 7(suppl 3):S349.

204. Kjellstrand CM, Arieff AI, Friedman EA, et al: Inadequacy of dialysis: Why patients are not well. Trans Am Soc Artif Intern Organs 1979; XXV:518-520.

205. Vanholder R, DeSmet R, Hsu C, et al: Uremic toxins: The middle molecule hypothesis revisited. Semin Nephrol 1994; 14:205-218.

206. Sato Y, Kaji M, Metoki N, et al: Does compensatory hyperparathyroidism predispose to ischemic stroke?. Neurol 2003; 60:626-629.

207. Wanner C, Zimmermann J, Schwedler S, Metzger T: Inflamation and cardiovascular risk in dialysis patients. Kidney Int 2002; 61(suppl 80):S99-S102.

208. Makita Z, Radoff S, Rayfield EJ, et al: Advanced glycosylation end products in patients with diabetic nephropathy. N Engl J Med 1991; 325:836-842.

209. Haag-Weber M: AGE-modified proteins in renal failure. In: Ronco C, Bellomo R, ed. Critical Care Nephrology, Hingham, MA: Kluwer Academic Publishers; 1998:878-883.

210. Miyata T, van Ypersele de Strihou C, Ueda Y, et al: Angiotensin II receptor antagonists and angiotensin-converting enzyme inhibitors lower in vitro the formation of advanced glycation end products: Biochemical mechanisms. J Am Soc Nephrol 2002; 13:2478-2487.

211. Koenig H, Goldstone AD, Lu CY, Trout JJ: Polyamines: Transducers of osmotic signals at the blood-brain barrier. Proc Am Soc Neurochem 1988; 19:79.

212. Clements RSJ, DeJesus PVJ, Winegrad AI: Raised plasma-myoinositol levels in uraemia and experimental neuropathy. Lancet 1973; 1:1137-1141.

213. Goldstein DA, Chui LA, Massry SG: Effect of parathyroid hormone and uremia on peripheral nerve calcium and motor nerve conduction velocity. J Clin Invest 1978; 62:88-92.

214. McQuillen MP, Gorin FJ: Serial ulnar nerve conduction velocity measurements in normal subjects. J Neurol Neurosurg Psychiatry 1969; 32:144.

215. Avram MM, Feingold DA, Huatuco AH: Search for the uremic toxin: Decreased motor nerve conduction velocity and elevated parathyroid hormone in uremia. N Engl J Med 1978; 298:1000.

216. Lonergan ET, Semar M, Sterzel RB, et al: Erythrocyte transketolase activity in dialyzed patients. N Engl J Med 1971; 284:1399.

217. Reznek RH, Salway JG, Thomas PK: Plasma myoinositol concentrations in uraemic neuropathy. Lancet 1977; 1:675.

218. Mallette LE, Pattern BM, Engle WK: Neuromuscular disease in secondary hyperparathyroidism. Ann Intern Med 1975; 82:474.

219. Giulio SD, Chkoff N, Lhoste F, et al: Parathormone as a nerve poison in uremia. N Engl J Med 1978; 299:1134-1135.

220. Aurbach GD: Neuromuscular disease in primary hyperparathyroidism. Ann Intern Med 1974; 80:182.

221. Asbury AK: Uremic Neuropathy, Philadelphia, Saunders, 1975.

222. Arnaud CD: Hyperparathyroidism and renal failure. Kidney Int 1973; 4:89.

223. De Boer IH, Gorodetskaya I, Young B, et al: The severity of secondary hyperparathyroidism in chronic renal insufficiency is GRF-dependent, race dependent, and associated with cardiovascular disease. J Am Soc Nephrol 2002; 13:2762-2769.

224. Goldstein DA, Massry SG: The relationship between the abnormalities in EEG and blood levels of parathyroid hormone in dialysis patients. J Clin Endocrinol Metab 1980; 51:130.

225. Rasmussen H, Goodman DBP: Relationships between calcium and cyclic nucleotides in cell activation: Cellular calcium metabolism and calcium-mediated cellular processes. Physiol Rev 1977; 57:428.

226. Kennedy AC, Linton AL, Eaton JC: Urea levels in cerebrospinal fluid after hemodialysis. Lancet 1962; 1:410.

227. Arieff AI: Dialysis disequilibrium syndrome: Current concepts on pathogenesis. In: Schreiner GE, Winchester JF, ed. Controversies in Nephrology, Washington, DC: George Washington University Press; 1982:367-376.

228. Arieff AI: Dialysis disequilibrium syndrome: Current concepts on pathogenesis and prevention. Kidney Int 1994; 45(3):629-635.

229. Pagel MD, Ahmad S, Vizzo JE, et al: Acetate and bicarbonate fluctuations and acetate intolerance during dialysis. Kidney Int 1982; 21:513.

230. Rodrigo F, Shideman J, McHugh R, et al: Osmolality changes during hemodialysis: Natural history, clinical correlations, and influence of dialysate glucose and intravenous mannitol. Ann Intern Med 1977; 86:554-561.

231. Van Stone JC, Carey J, Meyer R, Murrin C: Hemodialysis with glycerol containing dialysate. ASAIO J 1979; 2:119-123.

232. Grushkin CM, Korsch B, Fine RN: Hemodialysis in small children. JAMA 1972; 221:869.

233. de Peterson H, Swanson AG: Acute encephalopathy occurring during hemodialysis. Arch Intern Med 1964; 113:877.

234. Fukusige M, Tado O, Matsuki S, et al: Hemodialysis with kill-type artificial kidney: Clinical study on disequilibrium syndrome. Acta Urol Jap 1971; 17:89.

235. Mawdsley C: Neurological complications of hemodialysis. Proc R Soc Med 1972; 65:871.

236. Porte FK, Johnson WJ, Klass DW: Prevention of dialysis disequilibrium syndrome by use of high sodium concentration in the dialysate. Kidney Int 1973; 3:327.

237. Arieff AI, Leach W, Park R, Lazarowitz VC: Systemic effects of NaHCO3 in experimental lactic acidosis in dogs. Am J Physiol 1982; 242:F586-F591.(Renal Fluid Electrolyte Physiol 11)

238. Greca G, Dettori P, Biasoli S: Brain density studies in dialysis. Lancet 1980; 2:582.

239. Paganini EP: General application of continuous therapeutic techniques. In: Henrich WL, ed. Principles and Practice of Dialysis, Baltimore: Williams & Wilkins; 1994:98-110.

240. Kliger AS: Complications of dialysis: Hemodialysis, peritoneal dialysis and CAPD. In: Arieff AI, DeFronzo RA, ed. Fluid, Electrolyte and Acid-Base Disorders, New York: Churchill Livingstone; 1985:777-826.

241. Rouby JJ, Rottenbourg J, Durande JP: Hemodynamic changes induced by regular hemodialysis and sequential ultrafiltration hemodialysis: A comparative study. Kidney Int 1980; 17:801.

242. Oliver MJ, Edwards LJ, Churchill DN: Impact of sodium and ultrafiltration profiling on hemodialysis-related symptoms. J Am Soc Nephrol 2001; 12:151-156.

243. Arieff AI, Lazarowitz VC, Guisado R: Experimental dialysis disequilibrium syndrome: Prevention with glycerol. Kidney Int 1978; 14:270-278.

244. Burkart J: Adequacy of peritoneal dialysis. In: Henrich WL, ed. Principles and Practice of Dialysis, Baltimore: Williams & Wilkins; 1994:111-129.

245. Gutman RA, Blumenkrantz MJ, Chan YK: Controlled comparison of hemodialysis and peritoneal dialysis: Veterans Administration multicenter study. Kidney Int 1984; 26:459-470.

246. Mahurkar SD, Dkar SK, Salta R, et al: Dialysis dementia. Lancet 1973; 1:1412-1415.

247. Alfrey AC, Mishell J, Burks SR, et al: Syndrome of dysphaxia and multifocal seizures associated with chronic hemodialysis. Trans Amer Soc Artif Intern Organs 1972; 18:257-261.

248. Barratt LJ, Lawrence JR: Dialysis-associated dementia. Aust N Zeal J Med 1975; 5:62-65.

249. Chokroverty S, Bruetman ME, Berger V, Reyes MG: Progressive dialytic encephalopathy. J Neurology Neurosurgery Psychiatry 1976; 39:411-419.

250. Mahurkar SD, Myers L, Cohen J, et al: Electroencephalographic and radionucleotide studies in dialysis dementia. Kidney Int 1978; 13:306-315.

251. Nadel AM, Wilson WP: Dialysis encephalopathy: A possible seizure disorder. Neurology 1976; 26:1130-1134.

252. Noriega-Sanchez A, Martinez-Maldonado M, Haiffe RM: Clinical and electroencephalographic changes in progressive uremic encephalopathy. Neurology 1978; 28:667-669.

253. Dunea G, Mahurkar SD, Mamdami B: Role of aluminum in dialysis dementia. Ann Intern Med 1978; 88:502-504.

254. Flendrig JA, Kruis H, Das HA: Aluminum and dialysis dementia. Lancet 1976; 1:235.

255. Alfrey AC, LeGendre GR, Kaehny WD: The dialysis encephalopathy syndrome: Possible aluminum intoxication. N Engl J Med 1976; 294:184-188.

256. McDermott JR, Smith AI, Ward MK, et al: Brain aluminum concentration in dialysis encephalopathy. Lancet 1978; 1:901.

257. Parkinson ID: Fracturing dialysis osteodystrophy and dialysis encephalopathy. Lancet 1979; 1:406.

258. Arieff AI, Cooper JD, Armstrong D, Lazarowitz VC: Dementia, renal failure and brain aluminium. Ann Intern Med 1979; 90:741-747.

259. Cartier F, Allain P, Gary J, et al: Encephalopathie myoclonique progressive des dialyses: Role de l'eau utilisee pour l'hemodialyse. Nouv Presse Med 1978; 7:97-102.

260. Burks JS, Alfrey AC, Huddlestone J, et al: A fatal encephalopathy in chronic haemodialysis patients. Lancet 1976; 1:764-768.

261. Ward MK, Feest TG, Ellis HA, et al: Osteomalacic dialysis osteodystrophy: Evidence for a water-borne aetiological agent, probably aluminum. Lancet 1978; 1:841.

262. Pierides AM, Edwards Jr WG, Cullum Jr UX, et al: Hemodialysis encephalopathy with osteomalacic fractures and muscle weakness. Kidney Int 1980; 18:115.

263. Prior JC, Cameron EC, Knickerbocker WJ, et al: Dialysis encephalopathy and osteomalacic bone disease. Am J Med 1982; 72:33.

264. Arieff AI: Aluminum and the pathogenesis of dialysis dementia. Environ Geochem Health 1990; 12(1/2):89-93.

265. Fraser CL, Arieff AI: Nervous system manifestations of renal failure. In: Schrier RW, Gottschalk CW, ed. Diseases of the Kidney, 5th ed. Boston, MA: Little, Brown & Co; 1993:2789-2816.

266. Thodis E, Anninos PA, Pasadakis P, et al: Evaluation of CNS function in CAPD patients using magnetoencephalography (MEG). Advances Peritoneal Dialysis 1992; 8:181-184.

267. Farrar G, Altmann P, Welch S, et al: Defective gallium-transferrin binding in Alzheimer disease and Down syndrome: Possible mechanism for accumulation of aluminum in brain. Lancet 1990; 335:747-750.

268. Farrar G, Morton AP, Blair JA: The intestinal spectiation of gallium: Possible models to describe the bioavailability of aluminum. In: Bratter P, Schramel P, ed. Trace Element Analytical Chemistry in Medicine and Biology, Berlin: Walter de Gruyter; 1988:343-347.

269. Brun A, Dictor M: Senile plaques and tangles in dialysis dementia. Acta Path Microbiol Scand Sect A 1981; 89:193-198.

270. Altmann P, Al-Salihi F, Butter K, et al: Serum aluminum levels and erythrocyte dihydropteridine reductase activity in patients on hemodialysis. N Engl J Med 1987; 317:80-84.

271. Chazan JA, Blonsky SL, Abuelo JG, Pezzullo JC: Increased body aluminum: An independent risk factor in patients undergoing long-term hemodialysis?. Arch Intern Med 1988; 148:1817-1820.

272. Sprague SM, Corwin HL, Tanner CM, et al: Relationship of aluminum to neurocognitive dysfunction in chronic dialysis patients. Arch Intern Med 1988; 148:2169-2172.

273. Altmann P, Hamon C, Blair J, et al: Disturbance of cerebral function by aluminum in haemodialysis patients without overt aluminum toxicity. Lancet 1989; ii:7-12.

274. Emmett M, Sirmon MD, Kirkpatrick WG, et al: Calcium acetate control of serum phosphorus in hemodialysis patients. Am J Kidney Dis 1991; 17:544-550.

275. Mai ML, Emmett M, Sheikh MS, et al: Calcium acetate, an effective phosphorus binder in patients with renal failure. Kidney Int 1989; 36:690-695.

276. Slatopolsky EA: Renagel®, a nonabsorbed calcium- and aluminum-free phosphate binder, lowers serum phosphorus and parathyroid hormone. Kidney Int 1999; 55:299-307.

277. Perl DP, Good PF: Uptake of aluminum into central nervous system along nasal-olfactory pathways. Lancet 1987; 329:1028.

278. Rifat SL, Eastwood MR, McLachlan DRC, Corey PN: Effect of exposure of miners to aluminum powder. Lancet 1990; 336:1162-1165.

279. Campbell IR, Cass JF, Cholak J: Aluminum in the enviornment of man. AMA Arch Indust Health 1957; 15:359-361.

280. Persy VP, Behets GJ, Bervoets AR, et al: Lanthanum; A safe phosphate binder. Semin Dialy 2006; 19:995-999.

281. Finn WF: Lanthanum carbonate versus standard therapy for the treatment of hyperphosphatemia: Safety and efficacy in chronic maintenance hemodialysis patients. Clin Nephrol 2006; 65:191-202.

282. Good PF, Perl DP: A laser microprobe mass analysis study of aluminum distribution in the cerebral cortex of dialysis encephalopathy. J Neuropathol Exp Neurol 1988; 47:321.

283. Collins AJ: High-flux, high-efficiency procedures. In: Henrich WL, ed. Principles and Practice of Dialysis, Baltimore: Williams & Wilkins; 1994:76-88.

284. Banks WA, Kastin AJ: Aluminium increases permeability of the blood-brain barrier to labelled DSIP and b endorphin: Possible implications for senile and dialysis dementia. Lancet (Nov. 26) 1983;1227-1229.

285. Wing AJ: Dialysis dementia in Europe: Report from the registration committee of the EDTA. Lancet 1980; 1:190.

286. Berkseth RO, Shapiro FL: An epidemic of dialysis encephalopathy and exposure to high aluminum dialysate. In: Schriener GE, Winchester JF, ed. Controversies in Nephrology, Georgetown, MD: Georgetown University Press; 1980:42.

287. Arieff AI: Effects of water, acid base, and electrolyte disorders on the central nervous system. In: Arieff AI, DeFronzo RA, ed. Fluid, Electrolyte and Acid-Base Disorders, New York: Churchill Livingstone; 1985:969-1040.

288. Graf H, Stummvoll HK, Messinger V: Aluminum removal by hemodialysis. Kidney Int 1981; 19:587.

289. Kaehny WD, Hegg AP, Alfrey AC: Gastrointestinal absorption of aluminum from aluminum-containing antacids. N Engl J Med 1977; 296:1389-1390.

290. Sedman AB, Wilkening GN, Warady BA: Encephalopathy in childhood secondary to aluminum intoxication. J Pediatr 1984; 105:836-838.

291. Sedman AB, Klein GL, Merritt RJ, et al: Evidence of aluminum loading in infants receiving intravenous therapy. N Engl J Med 1985; 312:1337-1343.

292. Santos F, Massie MD, Chan JCM: Risk factors in aluminum toxicity in children with chronic renal failure. Nephron 1986; 42:189-195.

293. Salusky IB, Foley J, Nelson P, Goodman WG: Aluminum accumulation during treatment with aluminum hydroxide and dialysis in children and young adults with chronic renal disease. N Engl J Med 1991; 324:527-531.

294. Polinsky MS, Gruskin AB: Aluminum toxicity in childhood secondary to aluminum toxicity. J Pediatr 1984; 105:758-761.

295. Andreoli SP, Bergstein JM, Sherrard DJ: Aluminum intoxication from aluminum-containing phosphate binders in children with azotemia not undergoing dialysis. N Engl J Med 1984; 310:1079.

296. Perl DP, Brody AR: Alzheimer's disease: X-ray spectrometric evidence of aluminum accumulation in neurofibrillary tangle-bearing neurons. Science 1980; 208:297-299.

297. Kogeorgos J, Scholtz C: Neurofibrillary tangles in aluminum encephalopathy: A new finding. Neuropathol Appl Neurobiol 1982; 8:246.

298. Garruto RM, Fukatsu R, Yanagihara R, et al: Imaging of calcium and aluminum in neurofibrillary tangle-bearing neurons in parkinsonism-dementia of Guam. Proc Natl Acad Sci U S A 1983; 81:1875-1879.

299. Candy JM, McArthur FK, Oakley AE, et al: Aluminum accumulation in relation to senile plaque and neurobibrillary tangle formation in the brains of patients with renal failure. J Neurol Sci 1992; 107:210-218.

300. Katzman R: Alzheimer's disease. N Engl J Med 1986; 314:964-973.

301. Arieff AI, Mahoney CA: Pathogenesis of dialysis encephalopathy. Neurobehav Toxicol Teratol 1983; 5(6):641-644.

302. Berlyne GM, Ben-Ari J, Pest D: Hyperaluminemia from aluminum resins in renal failure. Lancet 1970; 2:494.

303. Mayor GH, Sprague SM, Hourani MR, Sanchez TV: Parathyroid hormone-mediated aluminum deposition and egress in the rat. Kidney Int 1980; 17:40-44.

304. Cantin M, Genest J: The heart and the atrial natriuretic factor. Endocrinol Rev 1985; 6:107-127.

305. Mathew RJ, Rabin P, Stone WJ, Wilson WH: Regional cerebral blood flow in dialysis encephalopathy and primary degenerative dementia. Kidney Int 1985; 28:64-68.

306. Malluche HH, Smith AJ, Abreo K: The use of deferoxamine in the management of aluminum accumulation in bone in patients with renal failure. N Engl J Med 1984; 311:140.

307. Passer JA: Cerebral atrophy in end-stage uremia. Proc Clin Dialy Trans Forum 1977; 7:91.

308. Smith JS: The investigation of dementia: Results in 200 consecutive admissions. Lancet 1981; 1:824.

309. Gajdusek DC: Hypothesis: Interference with axonal transport of neurofilament as a common pathogenetic mechanism in certain diseases of the central nervous system. N Engl J Med 1985; 312:714-719.

310. Selkoe DJ: Cerebral aging and dementia. In: Tyler HR, Dawson DM, ed. Current Neurology, Boston: Houghton Mifflin; 1978:360-387.

311. Drueke T: Aluminum toxicity in chronic renal failure. J Nephrol 1989; 1:49-57.

312. Rotter W, Roettger P: Comparative pathologic-anatomic study of cases of chronic global renal insufficiency with and without preceding hemodialysis. Clin Nephrol 1974; 1:257.

313. Kucharczyk W, Brant-Zawadzki M, Norman D: Magnetic resonance imaging of the central nervous system-An update. West J Med 1985; 142:54-62.

314. Weber DL, Reagan T, Leeds M: Intracerebral hemorrhage during hemodialysis. N Y State J Med 1972; 72:1853.

315. Bleumle LW: Current status of chronic hemodialysis. Am J Med 1968; 44:749.

316. Smith RJ, Block MR, Arieff AI, et al: Hypernatremic, hyperosmolar coma complicating chronic peritoneal dialysis. Proc Clin Dialysis Trans Forum 1974; 4:96-99.

317. Arieff AI: Central nervous system manifestations of disordered sodium metabolism. In: Morgan DB, ed. Clinics in Endocrinology and Metabolism: Electrolyte Disorders, Philadelphia: WB Saunders; 1984:269-294.

318. Bolton CF: Electrophysiologic changes in uremic neuropathy after successful renal transplantation. N Engl J Med 1976; 284:1170.

319. Bolton CF, Baltzan MA, Baltzan RB: Effects of renal transplantation on uremic neuropathy. N Engl J Med 1971; 26:1170.

320. Anderson RJ, Schafer LA, Olin DB: Infectious risk factors in the immunosuppressed host. Am J Med 1973; 54:453.

321. Caplan LR, Hacke W: Acute ischemic stroke. In: Brandt T, Caplan LR, Dichgans J, et al ed. Neurological Disorders: Course and Treatment, 2nd ed. London: Academic Press; 2003:327-347.

322. Griggs RC, Arieff AI: Hypoxia and the central nervous system. In: Griggs RC, Arieff AI, ed. Metabolic Brain Dysfunction in Systemic Disorders, Boston: Little, Brown and Co.; 1992:39-54.

323. Vink R, McIntosh TK, Demediuk P, et al: Decline in intracellular free Mg2+ is associated with irreversible tissue injury after brain trauma. J Biol Chem 1988; 263(2):757-761.

324. Cheung JY, Bonventre JV, Malis CD, Leaf A: Calcium and ischemic injury. N Engl J Med 1986; 314(26):1670-1676.

325. Kernan WN, Viscolli CM, Brass LM, Broderick JP: Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med 2000; 343:1826-1832.

326. Bachelard HS: The molecular basis of coma and stroke. In: Cohen RD, Lewis B, Alberti KGMM, Denman AM, ed. The Metabolic and Molecular Basis of Acquired Disease, Philadelphia and London: WB Saunders/Baillière Tindall; 1990:1354-1380.

327. Amarenco P, Duyckaerts C, Tzourio C, et al: The prevalence of ulcerated plaques in the aortic arch in patients with stroke. N Engl J Med 1992; 326:221-225.

328. Iseki K, Kawazoe N, Osawa A: Survival analysis of dialysis patients in Okinawa, Japan (1971-1990). Kidney Int 1993; 43:404-409.

329. Mazzuchi N, Carbonell E, Fernandez-Caen J: Importance of blood pressure control in hemodialysis patient survival. Kidney Int 2000; 58:2147-2154.

330. Rostand SG, Brunzell JD, Cannon RO, Victor RG: Cardiovascular complications in renal failure. J Am Soc Nephrol 1991; 2:1053-1062.

331. Held PJ, Brunner F, Okada M, Garcia JR: Five year survival for end stage renal disease patients in the USA, Europe and Japan, 1982-1987. J Am Soc Nephrol 1990; 15:451-457.

332. Breyer JA: Medical management of nephropathy in type I diabetes mellitus: Current recommendations. J Am Soc Nephrol 1995; 6:1523-1529.

333. Foley RN, Harnett JD, Parfrey PS: Cardiovascular complications of end-stage renal disease. In: Schrier RW, Gottschalk CW, ed. Diseases of the Kidney, 6th ed. Boston: Little, Brown & Co.; 1997:2647-2660.

334. Orth DN, Kovacs WJ: The adrenal cortex. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, ed. Williams Textbook of Endocrinology, Philadelphia: WB Saunders Co.; 1998:517-664.

335. Bronner LL, Kanter DS, Manson JE: Primary prevention of stroke. N Engl J Med 1995; 333:1392-1400.

336. Zimmerman JS, Herringer JS: Inflamation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int 1999; 55:648-658.

337. Shulman AI, Mangelsdorf DJ: Retinoid X receptor heterodimers in the metabolic syndrome. N Engl J Med 2005; 353:604-615.

338. Shoelson SE: Inflamation and insulin resistance. J Clin Invest 2006; 116:1793-1799.

339. Shlipak MG, Sarnak MJ, Katz R: Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med 2005; 352:2049-2060.

340. Shlipak MG, Fried LF, Cushman M, Manolio TA: Cardiovascular mortality risk in chronic kidney disease: Comparison of traditional and novel risk factors. JAMA 2005; 293:1737-1745.

341. Astor BC, Coresh J, Heiss G, et al: Kidney function and anemia as risk factors for coronary heart disease and mortality. Am Heart J 2006; 151:492-500.

342. Abramson JL, Jurkovitz CT, Vaccarino V, et al: Chronic kidney disease, anemia, and incident stroke in a middle-aged community-based population: The ARIC study. Kidney Int 2003; 64:610-615.

343. Brooks MM, Frye RL, Genuth S, et al: Hypothesis, design, and methods for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BRI 2D) trial. Am J Cardiol 2006; 97(12A):9G-19G.

344. Groschel K, Ernemann U, Schultz JB, et al: Statin therapy at carotid angioplasty and stent placement: Effect on procedure-related stroke, myocardial infarction, and death. Radiology 2006; 240:145-151.

345. Bennett MH, Wasaik J, French C, et al: Hyperbaric oxygen therapy for acute ischemic stroke. Stroke 2006; 37:1953.

346. Habib GB: Prevention of vascular events in patients with cerebrovascular disease: efficacy and appropriate duration of antiplatelet therapy. Clin Cardiol 2006; 29:244-248.

347. Weintraub MI: Thronbolysis (tissue plasminogen activator) in stroke: A medicolegal quagmire. Stroke 2006; 37:1917-1922.

348. Alexandrov AV, Molina CA, Grotta JC, Wojner AW: Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med 2004; 351:2170-2178.

349. Touze E, Varenne O, Chatellier G, et al: Risk of myocardial infarction and vascular death after transient ischemic stroke. Stroke 2005; 36:2748-2755.

350. Collins RC, Dobkin BH, Choi DW: Selective vulnerability of the brain: New insights into the pathophysiology of stroke. Ann Intern Med 1989; 110(12):992-1000.

351. Miyata T, Inagi R, Iida Y, et al: Involvement of B2-microglobulin modified with advanced glycosylation end products in the pathogenesis of hemodialysis-associated amyloidosis. J Clin Invest 1994; 93:521-528.

352. Ronco C, Brendolan A, Bellomo R: Current technology for continuous renal replacement therapies. In: Ronco C, Bellomo R, ed. Critical Care Nephrology, Hingham, MA: Kluwer Academic Publishers; 1998:1269-1308.

353. Cohen HJ, Harris T, Pieper CF: Coagulation and development of inflamatory pathways in the development of functional decline and mortality in the elderly. Am J Med 2003; 114:180-187.

354. Beddhu S, Allen-Brady K, Cheung AK, et al: Impact of renal failure on the risk of myocardial infarction and death. Kidney Int 2002; 62:1776-1783.

355. Brott T, Bogousslavsky J: Treatment of acute ischemic stroke. N Engl J Med 2000; 343:710-722.

356. Beal MF: Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses?. Ann Neurol 1992; 31:119-130.

357. Kumar M, Liu GJ, Floyd RA, Grammas P: Anoxic injury of endothelial cells increses production of nitric oxide and hydroxyl radicals. Biochem Biophys Res Comm 1996; 219:497-501.

358. Kurose I, Wolf R, Grisham MH, et al: Microvascular responses to inhibition of nitric oxide production: Role of active oxidants. Circ Res 1995; 76:30-39.

359. Aortic plaques in stroke FSG. Atherosclerotic disease of the aortic arch as a risk foactor for recurrent ischemic stroke. N Engl J Med 1996; 334:1216-1221.

360. Vidaillet H, Granada JF, Chyou PH, Maassen K: A population-based study of mortality among patients with atrial fibrillation or flutter. Am J Med 2002; 113:365-370.

361. Penado S, Cano M, Acha O, et al: Atrial fibrillation as a risk factor for stroke recurrence. Am J Med 2003; 114:206-210.

362. Goadsby PJ, Lipton RB, Ferari MD: Migraine—Current understanding and treatment. N Engl J Med 2002; 346:257-270.

363. Lieberman EH, Gerhard MD, Uehata A, et al: Estrogen improves endothelium-dependent, flow-mediated vasodilation in postmenopausal women. Ann Intern Med 1994; 121:936-941.

364. Riggs Bl, Hartmann LC: Selective estrogen-receptor modulators—mechanism of action and application to clinical practice. N Engl J Med 2003; 348:618-629.

365. WHII WG: Risks and benefits of estrogen plus progestin in healthy post-menopausal women. JAMA 2002; 288:321-333.

366. Appel LJ: The verdict from ALLHAT. JAMA 2002; 288:3039-3041.

367. ALLHAT: Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. JAMA 2002; 288:2981-2997.

368. Lewis EJ, Hunsicker LG, Clarke WR, et al: Renoprotective effect of the angiotensin-receptor antagonist irbosartan in patients with Nephropathy due to type 2 diabetes. N Engl J Med 2001; 345:851-860.

369. Campbell R, Sangalli F, Perticucci E, et al: Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies. Kidney Int 2003; 63:1094-1103.

370. Kucharczyk J, Mintorovitch J, Moseley ME, et al: Ischemic brain edema is reduced by a novel calcium and sodium channel entry blocker. Radiology 1991; 179:221-227.

371. Kucharczyk J, Chew W, Derugin N, Moseley ME: Nicardipine reduces ischemic brain injury. Magnetic resonance imaging/spectroscopy study in cats. Stroke 1989; 20(2):268-274.

372. Albers GW, Atkinson RP, Kelley RE, Rosenbaum DM: Safety, tolerability and pharmacokinetics of the NMDA antagonist dextrorphan in patients with acute stroke. Stroke 1995; 26:254-258.

373. Gress DR: Stroke: Revolution in therapy. West J Med 1994; 161:288-291.

374. Parfrey PS, Griffiths SM, Barrett BJ, et al: Contrast material-induced renal failure in patients with diabetes mellitus, renal insufficiency, or both. A prospective controlled study. N Engl J Med 1989; 320:143-149.

375. Study Group E : Thrombolytic therapy with streptokinase in acute ischemic stroke. N Engl J Med 1996; 335:145-150.

376. rt-PA Stroke Study Group N : Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333:1581-1587.

377. del Zoppo GJ: Acute stroke—on the threshold of a therapy. N Engl J Med 1995; 333:1632-1633.

378. Sherman DG, Atkinson RP, Chippendale T: Intravenous ancrod for treatment of acute ischemic stroke. JAMA 2000; 283:2395-2403.

379. Yasuda H, Nakajiima A: Brain protection against ischemic injury by nizofenone. Cerebrovasc Brain Metabol Rev 1993; 5:264-268.

380. Schievink WI: Spontaneous dissection of the carotid and vertebral arteries. N Engl J Med 2001; 344:898-906.

381. Schievink WI, Mokri B, O'Fallon WM: Recurrent spontaneous cervical-artery dissection. N Engl Med 1994; 330:393-397.

382. Chass M: Pitcher's autopsy points to ephedra as one factor. New York Times March 2003; 14:C17.

383. Haller CA, Benowitz NL: Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med 2000; 343:1833-1838.

384. Droller MJ, Anderson JR, Beck JC: Impotence. JAMA 1993; 270:83-90.

385. Campese VM, Romoff MS, Levitan D: Mechanisms of autonomic nervous system dysfunction in uremia. Kidney Int 1981; 20:246.

386. Massry SG, Bellinghieri G: Sexual dysfunction. In: Massry SG, Glassock RJ, ed. Textbook of Nephrology, 3rd ed. Baltimore: Williams & Wilkins; 1995:1416-1421.

387. Lamberts SWJ, van den Beld AW, van der Lely A: The endocrinology of aging. Science 1997; 278:419-424.

388. Sharma RK, Prasad N, Gupta A, Kapoor R: Treatment of erectile dysfunction with sildenafil citrate in renal allograft recipients. Am J Kidney Dis 2006; 48:128-133.

389. Campese VM, Liu CL: Sexual dysfunction in uremia. Contrib Nephrol 1990; 77:1-14.

390. Leland J: A pill for impotence?. Newsweek 1997;Nov; 17:62-68.

391. Nathan HP, Hellstrom WJG, Kaiser FE: Treatment of men with erectile dysfunction with transurethral alprostadil. N Engl J Med 1997; 336:1-7.

392. Herrmann HC, Chang G, Klugherz BD, Mahoney PD: Hemodynamic effects of sildenafil in men with severe coronary artery disease. N Engl J Med 2000; 342:1622-1626.

393. Utiger RD: A pill for impotence. N Engl J Med 1998; 338:1458-1459.

394. Seibel I, De Figueiredo CEP, Teloken C, Moraes JF: Efficacy of oral sildenafil in hemodialysis patients with erectile dysfunction. J Am Soc Nephrol 2002; 13:2770-2775.

395. Nielsen VK: The peripheral nerve function in chronic renal failure. VI. Acta Med Scand 1973; 194:455.

396. Raskin NH, Fishman RA: Neurologic disorders in renal failure. N Engl J Med 1976; 294:143.

397. Robinson TG, Carr SJ: Cardiovascular autonomic dysfunction in uremia. Kidney Int 2002; 62:1921-1932.

398. Fernandez JP, McGinn JT, Hoffman RS: Cerebral edema from blood-brain glucose differences complicating peritoneal dialysis second membrane syndrome. N Y State J Med 1968; 68:677.

399. Schneck SA: Neuropathological features of human organ transplantation 1. J Neuropathol Exp Neurol 1965; 24:415.

400. Spencer PS, Schaumberg HH: Central peripheral distal axonopathy—The pathology of “dying-back” polyneuropathies. Prog Neuropathol 1977; 3:255.

401. Thomas PK, Hollinrake K, Lascelles RG: The polyneuropathy of chronic renal failure. Brain 1971; 94:761.

402. Spencer PS, Sabri MI, Schaumberg HH: Does a defect of energy metabolism in the nerve fiber underlie axonal degeneration in polyneuropathies?. Ann Neurol 1979; 5:501.

403. Calcutt NA, Allendoerfer KL, Mizisin AP, Middlemas A: Therapeutic efficacy of sonic hedgehog protein in experimental diabetic neuropathy. J Clin Invest 2003; 111:507-514.

404. Tyler HR: Neurologic disorders seen in the uremic patient. Arch Intern Med 1970; 126:781-786.

405. Blagg CR, Kemble F, Taverner D: Nerve conduction in relationship to the severity of renal disease. Nephron 1968; 5:290.

406. Blumberg A, Esslen E, Burgi W: Myoinositol-Uremic neurotoxin?. Nephron 1978; 21:186.

407. Man NK, Terlain B, Paris J, et al: An approach to “middle molecules” identification in artificial kidney dialysate, with reference to neuropathy prevention. Trans Am Soc Artif Intern Organs 1973; 19:320.

408. Kjellstrand CM, Arieff AI, Friedman EA, et al: Considerations of the middle molecule hypothesis II. Trans Am Soc Artif Intern Organs 1973; 19:325.

409. Kanda F, Jinnai K, Tada K, et al: Somatosensory evoked potentials in acute renal failure. Kidney Int 1990; 38:1085.

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