OMG LINKME

Tastes Like Depeche Mode
Philly from the Inside out
Funny: Where It's At
Actually Useful for Something
Philly Blah, Blah and more Blah.

All materials on this page are written by Byron Kho and are his sole property, or jointly shared with the co-authors listed. Materials are unpublished but have appeared in internal reviews and grants. For permission to quote or a list of citations for each essay, please contact him at mail@byronkho.com.

Kidney Failure, Dialysis and Effects on Sensory Systems

I. The Kidney: Function and Dysfunction

The nephritic system centralized in the kidneys is extremely important in the proper maintenance of electrolytic levels in the blood. Additionally, they assist in regulating certain hormones and in removing waste products from the blood. Most of these processes occur due to fluid regulation within the nephrons. Water, ions and small molecules filter through capillary walls from the glomerulus into the Bowman’s capsule. From this nephric filtrate, glucose, amino acids, most of the uric acid and 60% of the inorganic salts are reabsorbed by active transport. The flow of sodium is controlled by the hormone angiotensin II, and phosphate removal by parathyroid hormone. As these are being removed, most of the 180 liters entering the kidneys in 24 hours gets removed by osmosis. Following this, more sodium is reclaimed in the distal tubules by the action of aldosterone. This last 3% controls water content and blood pressure in the body. Reclamation of urea is 50% - from 0.03 g/100 mL of plasma, it is concentrated to 1.8 g/100 mL in the urine. Likewise, uric acid goes from 0.004 g/100 mL in the plasma to 0.5 g/100 mL in the urine. All of the glucose and amino acids is reclaimed, unless the kidneys are damaged. Inorganic salts goes from 0.9 g/100 mL in the plasma to a maximum of 3.6 g/100 mL in the urine. Because proteins and other macromolecules are too large to be filtered, they remain in the blood.

If the kidneys are damaged by disease or stones, the nephrons become damaged and fluid retention and mineral levels are put off balance. In children, a majority of kidney diseases are caused by the hereditary passing of defective genes, which prevent normal kidney function and thus cause kidney disease. Older children sometimes get kidney failure by diseases that attack the glomeruli, the filters into the kidney that can allow blood and protein into the filtrate if damaged. The leading cause of kidney failure in adults is diabetes. Other leading causes include simultaneous high intake of caffeine and alcohol, as their combined diuretic properties can decrease water levels to dangerous levels.

Symptoms of kidney failure include generalized swelling, elevated blood pressure, pale skin, fatigue, shortness of breath, back pain, weakness, nausea, and uremia. Toxins or metabolites harmful at high levels that would normally be removed instead stick around and are directly responsible for many of these symptoms. As the blood brain barrier is weakened during kidney failure, many of these toxins can build up in the brain, causing neurological effects. Myoinositol, a precursor of phosphoinositide, is a prime candidate; dialysis does a poor job of removing this compound, but transplantation allows normal excretion again. Fluid retention is caused by sodium buildup. Parathyroid hormone have been directly linked to decreased survival of erythrocytes and other conditions, and has been shown to cause many of the nervous system abnormalities in dogs (Slatopolsky). In humans, it also allows retention of calcium (Massry). Since calcium is an important mediator of NT release, this can interfere with much intracellular activity. Some studies credit “middle molecules” of medium molecular weight with causation of neuropathies and uremia, as hemodialysis patients have more neuropathies than peritoneal dialysis patients (Tenckhoff, Babb). Peritoneal dialysis provides better clearance of middle molecules, because of a greater permeability to these substances.

Probably the most drastic associated condition is uremia, stemming from excessive amounts of urea and other nitrogenous compounds in the blood. Uremia is frequently terminal and usually involves nervous system complications, including impaired mental capacities, generalized weakness, sexual dysfunction and peripheral neuropathies. It is a multi-system disorder and leads to end-stage renal disease, where death is almost assured. Urea itself is non-toxic in low concentrations, but at higher concentrations (50-100 times normal), it can cause DNA strand breakage. It can cause skin irritation in humans. In cattle, who eat sometimes high-nitrogen feed, the urea can quickly break down into ammonia, causing hyperammonaemia and alkalosis. This can lead to death, or hyperexcitability, grinding, tremors, convulsions, dyspnea and comas. Urea is created when toxic ammonium combines with carbon in the liver; from there, it passes into the rest of the bloodstream to be removed by the kidneys. Saliva contains urea, so swallowing that enters urea into the GI tract. The brain even contains its own urea, which passes to the blood in different ways. In one method, urea goes directly through intra-parenchymal blood vessels. As well, interstitial area urea can be funneled through astrocytes and guided into the cerebrospinal fluid by endothelial cells. From there, it would then pass into the blood.

Uremic patients usually have elevated sodium and aluminum in the brain (Arieff 1973), with double the usual amount of calcium (Cooper). Also, uremic rat brains have been shown to be more permeable to inert molecules. Uremic patients frequently have higher brain osmolality – half of the increase is due to urea, and the other half, some indetermined solutes. Other studies show that uremic brains appear to use less ATP. Thus, less ADP, AMP and lactate should be produced, which is what results do show. Brain metabolic rates and cerebral oxygen consumption also decrease, pointing out a generalized decrease in brain energy use (Van den Noort). Furthermore, Na-K ATP pumps and calcium pumps within the brain seem to be altered, probably due to parathyroid hormone effects. This may affect information processing in the uremic patient (Fraser 1985). Individuals with polycystic kidney disease I tend to die or get ESRD at around 53 years, and those with polycystic kidney disease II at around 69.1 years. Also, primary response to kidney disease/failure (50-75% of 500,000 patients hospitalized for kidney failure are given diuretics) is associated with 68% increase in mortality and 77% increase in non-recovery of kidney function (Mehta).

II. Hemodialysis: Usage and Risks

Hemodialysis is an artificial filtering of the blood, to take over from what the kidneys cannot do. A gortex graft, or other methods of tubing, connects the dialysis machine to the blood supply using needles. The machine then utilizes different types of filters (cellulose acetate, hemophane) to remove waste and excess water from the blood. The process is required every couple days, and makes necessary strict diet and fluid control to ensure healthiness between sessions. Adequate dialysis is usually taken to mean a 2/3 removal of urea from the bloodstream. The urea (and other neurotoxins) can have effect between, and even during, dialysis sessions. Cardiac output from the kidneys goes mostly to the larger organs, but only 30% of the urea goes there. The rest goes to the muscle, skin and bones, which receive up to 70% of the urea.

One risk of dialysis (that can affect up to 7% of dialysis users) is a condition called dialysis disequilibrium syndrome (DDS). Because of the cerebral edema caused by water movement into the brain, patients suffer headaches, nausea, disorientation, restlessness, blurred vision, asterixis and even confusion, seizures, coma and death if severe (Burn). These symptoms develop during or immediately after hemodialysis. Hemodialysis rapidly removes small solutes like urea from the blood; the reduction in BUN and other similarly low-MW solutes lowers plasma osmolality creating a transient osmotic gradient that promotes water movement into the cells (Arieff 1978, Kennedy, Calons). This causes the edema. There is insufficient time for urea equilibration when hemodialysis rapidly reduces BUN, so the retention of brain urea in the interstices becomes an effective osmole, drawing water into the brain. This can also cause intracerebral acidosis. Elevated plasma osmolality may cause increased plasma ADH concentration and a lack of hyperintensity in the posterior pituitary gland, as shown by MRI (Sato). Another proposed cause is a decrease in intracellular pH of the cerebral cortex from increased production of organic acids (Arieff 1977). However, edema is a supported “side effect” of dialysis (Walters).

Some dialysis patients will get dialysis encephalopathy (known as dialysis dementia), a fatal neurologic disease (Agildere 2001). Symptoms include apraxia, speech slurring, stuttering, psychosis, dementia, seizures, and other conditions that worsen during dialysis (Burn). Death comes within 6 months. It exists in three forms. The sporadic endemic form has no known cure, has no clear relation to aluminum and occurs worldwide. The childhood form is probably due to uremic effects on an immature brain. The epidemic form only occurs in geographical clusters and is related to levels of elements in water used for dialysis, as it stops when the water is properly treated (Alfrey). Aluminum intoxication is the key suspect; levels of aluminum in the gray matter of dialysis dementia patients were higher than in normal dialysis patients. It is thought that a weakened or abnormal blood-brain barrier allows increased entry of aluminum into the brain. Encephalopathies of ALS, Parkinson’s and Alzheimer’s are thought to be related to increased aluminum levels as well (McDermott).

Two other conditions are less common. Thiamine deficiencies can cause Wernicke’s encephalopathy (Jagadha), but only result because of genetic predispositions, chronic malnourishment and use of glucose-containing IVs. Subdural hematomas can occur, in about 3% of all HD patients. Contributing factors include coagulation problems and the use of anticoagulants for dialysis (Raskin).

III. Association with Smell and Taste: Extent and Cause

One “side effect” of kidney failure is an overall drop in olfactory and gustatory function. Even at low levels of kidney impairment, there is an associated drop in olfactory and gustatory function unrelated to psychological impairment. While it has been known for many decades that there is a loss of taste associated with kidney disease (Burge 1984), it is only recently that papers have noted significant deficits in smell with renal patients (Griep). One paper suggests that many of the gustatory dysfunctions are in fact problems with smell (Deems). Studies of smell function after kidney failure generally accept that odor identification and discrimination are impaired (Frasnelli, Schiffman), but opinions differ to whether odor thresholds are similar or significantly different between controls and renal patients (Corwin, Griep). However, dual activation of the olfactory and trigeminal receptor system may be responsible for this difference. One study showed no difference in olfactory perceptions with activation of the trigeminal system (Vreman); another used a substance with minimal trigeminal effect and showed significant difference (Griep), supporting a deficiency in the olfactory receptor system in uremic patients. The trigeminal system is only activated by certain averse stimuli like ammonia, independent of the main olfactory system. Dialysis does not correct this impairment. Though it seems to improve taste function (Burge 1979), dialysis does not change or lowers olfactory ability (Conrad, Corwin).

What is responsible for this lowered odor perception, then? Low nutrient availability due to dialysis removal could limit receptor cell turnover rate and lead to that result (Schiffman), but as the problem occurs independent of dialysis treatment, this is unlikely. Most likely, it has to do with levels of toxins in the blood. Interestingly enough, transplantation returns olfaction and gustation to normal (Griep). This shows that materials in the blood being filtered – or not being filtered – are most probably responsible for the lowering of smell and taste perception. It has been proposed that urea might be one factor. The idea is that the effect of urea may be long-term, as urea removal by hemodialysis – or peritoneal dialysis – does not improve olfaction. Possibly, chronic exposure to urea limits smell ability and could take weeks to recover from, to explain the non-recovery after hemodialysis.

Another related factor are the neuropathies present in kidney damage and uremia (Fraser 1988). Typical effects include a slowing of conduction in the sensory nerves by demyelination and axonal degeneration, as well as problems with higher brain function. Uremic rats have shown altered or damaged calcium pumps (Fraser 1985), and as these mediate NT release in the CNS, this may affect information processing. Damage to other pumps supplying energy to the axons will result in neuron degeneration. Also, damage to the blood brain barrier allows differing amino acid concentrations in the cerebrospinal fluid and blood, which can cause synthesis of defective neurotransmitters (Cantaro). These neuropathies can be recovered from using dialysis, albeit very slowly, and full recovery is possible after transplantation (Burn) – which follows the course of olfactory and gustatory recovery. The direct effect of neuropathies on smell and taste include damage to the cranial nerves, which promote smell and taste information to the brain, and possibly subtle changes in brain processing that can impair tests of olfactory discrimination and identification (Conrad). For example, changes to the amygdala and hippocampus can change detection and response to averse stimuli. Zinc, associated with several of these neuropathies, occurs only in low amounts during renal failure; its restoration improves caloric intake and shows recovery of both neuronal function and taste acuity (Sprenger, Vreman).

IV. Imaging

As almost 30% of deaths of renal disease patients occur from cerebrovascular and cardiovascular complications, brain imaging can turn out to be quite important. These complications include strokes, subarachnoid and intracerebral hemorrhages and occlusive vascular disorders. Cranial MRI can not only detect signal intensities (to determine areas of neurologic disturbance) but it can determine the state of lesions, confirming or disconfirming diagnoses of encephalopathies or neuropathies (Schmidt). As well, it can detect silent cerebral infarctions, which are high risk factors for cerebrovascular diseases and occurred in almost 50% of the HD patients in one study (Nakatani). During kidney failure, the extent of the damage to the kidneys and to the blood brain barrier can be illustrated by MRI detection of an intravenous contrast medium. Normally, the contrast medium would be excreted by the kidneys, but with kidney failure, it can go elsewhere. Using T1-weighted imaging (T1 is the rate of magnetization recovery and differs between tissues), the contrast medium has been found to even enter the cerebrospinal fluid, meaning there has been leakage through the blood brain barrier (Zatman, Rai). Gadolinium is probably the most common contrast medium used with dialysis patients. It is non-protein-bound and can be excreted after 14 hours of dialysis; most doctors schedule dialysis within 24 hours of gadolinium injections (Choyke). An electrically neutral gadolinium chelate is often used, called gadobutrol. It has been found to be effectively removed from the blood after only three HD sessions using a low-flux polysulfone membrane (Tombach).

V. Nervous Complications of Uremia

A central manifestation of uremia is uremic encephalopathy, an organic brain syndrome whose symptoms span from anorexia and nausea to confusion, convulsions, stupor and coma. Their psychomotor behavior, thinking, memory, speech, perception and emotion are all affected (Teschan, Agildere 2001). Symptoms are alleviated by dialysis and are almost entirely relieved following successful renal transplantation (Raskin). However, memory and sleep disturbances may persist for the rest of the patient’s life. MRI is usually not useful in determining presence of this condition, but EEGs will usually show an abnormal state (Bolton). In most cases, it will be a generalized slowing.

Peripheral manifestations are known as uremic neuropathies and include loss of motor and sensory skills, with restless-leg syndrome, burning foot, and the loss of pain, vibration and touch modalities as premier symptoms (Schaumburg 1992). With time, weakness and wasting of limbs develop, and nerve conduction velocity decreases (Schaumburg 1979). This occurs in up to 65% of end-stage renal patients (Raskin). It is associated with a secondary demyelinating process of the spinal cord, which tends to affect the lower extremities more than the upper (Schaumburg 1979). It is thought that neurotoxins may deplete axonal energy supplies by inhibiting nerve fiber enzymes required for maintenance of energy synthesis. Resupply may fail to meet the increased demand, causing enzyme concentration to decrease in distal regions – which are most affected. This will lower axonal transport and cause a pathologic change in the nerves (Dyek). In the past, uremic neuropathies were considered primarily demyelinating conditions (Dinn), but the concentration of damage in the distal branches of the axon disproved that argument. The distal limbs are probably more vulnerable to neurotoxicity as they have lower temperatures, limiting enzymatic activity (Savazzi 1982). However, as uremic toxins can affect proximal and distal sites equally, a more encompassing explanation is necessary. The finding that myelin destruction is always associated with axon degeneration (Prineas) shows that demyelination results from axon or cell body damage. As data indicates resting potential falls (Cunningham) and there is greater surface area for toxin exposure on the axon, it is likely that the cause is damage to the axon. It cannot be forgotten, though, that axon damage can result from cell-body damage, as deficiencies and imbalances in the cell body can prevent proper trophic function within the axon (Savazzi 1982), leading to the demyelination. It should be kept in mind that hemodialysis reduces the incidence of severe uremic neuropathy

Osmotic demyelination syndrome or central pontine myelinolysis (CPM) is a demyelinative lesion in the central pons and extrapontine sites, because it is more vulnerable to edema than cerebral hemispheres (Killinc, Agildere 2001). Effects include disturbance of consciousness, quadriparesis, and mutism and has been considered to have a poor prognosis. MRI has revealed asymptomatic cases too. There are frequent abnormalities in serum electrolytes and osmolality, but there is no consensus as to which are pathogenic of CPM. Though the prognosis is usually fatal, MRI examinations of a few CPM follow-up patients showed reduction and resolution of lesions within a short time after dialysis (Kilinc), favoring transient edema rather than demyelination. Like DDS, blood chemistry suggests underlying changes in osmolality, probably resulting from urea reversal (Tarhan). One study found that CPM has definitive MRI findings, and neurological improvement is visible on MRI if and when it happens (Agildere 1998). Related brain edema episodes have also contributed to coma episodes in certain patients. While possibly related to heightened levels of ammonia and citrulline, the manifestations cleared up with intensified dialysis (Oshiro). Interestingly, high urea may also prevent myelinolysis induced by rapid correction of experimental hyponatremia, by inducing gene expression of myo-inositol and other osmolyte uptake transporters. This induction shortens a feedback loop, preventing subsequent osmolyte overshoot and demyelination (Soupart).

Dialysis-related hypotension seems to play a role in progressive frontal lobe atrophy in hemodialysis patients; the decrease in the frontal atrophy index for several patients over three years correlated significantly with number of hypotension episodes and increase in number of lacunae (Mizumasa). Also, rapid progression of the atrophy was related to and possibly caused by asymptomatic cerebral ischemia, only evidenced by brain lesions visible with MRI (Yoshimitsu). Lesions found are typically focal white matter lesions (Geissler). Metabolic alterations possibly contributing include higher choline to creatine ratios and higher myo-inositol and glycine to creatine ratios in the grey matter, and lowered N-acetylaspartate to creatine ratios within the white matter (Geissler).

VI. Effects on Sensory and Motor Systems

1) Visual System: One study reported a case of visual loss from posterior ischemic optic neuropathy after hemodialysis; MRI scan showed small vessel ischemic white matter changes. This complication is associated with anemia and hypotension (Buono, Servilla). The defective gene causing kidney disease in Alport syndrome can also cause hearing and vision loss. Several reports also credit subsequent hemodialysis treatments with a reversal of visual neuropathic effects (Saini, Knox). Children with renal failure can get pseudotumor cerebri, a condition that can cause visual loss as well as torticoloois, inattentiveness, facial paresis and new-onset strabismus (Belson). The cause of these injuries tends to be independent of dialysis modalities (Diaz-Buxo) and instead linked to usage of degrading membranes in old dialyzers (Hutter), cases of aluminum overload and subsequent treatment with desferrioxamine (Ravelli) and other conditions that have nothing to do with dialysis treatments. These many include long-term hypertension, hyperlipidemia, hypercalcemia, atherosclerosis and abnormal blood flow due to arteriovenous fistula (Terada). Certain exceptions found that hemodialysis treatments were linked to changes in contrast sensitivity (Woo) and changes in refraction in a majority of patients, forcing them to wear eyeglasses (Tomazzoli). Due to a multitude of reasons, most visual effects during hemodialysis show definite heterogeneity (Hamed).

2) Movement: One study reported that dialysis subjects were weaker, less active, and moved more slowly than controls. The muscle tissue in the legs of hemodialysis patients tended to atrophy, causing much of the loss in performance (Johansen 2003). The amount of atrophy is related to age and to dialysis dose (Johansen 2001). However, this may have a mental component too, as exercise regimes can reportedly increase objective measures of physical functioning, such as level of muscle atrophy (Painter 2000, Deligiannis, Kouidi), and metabolic abnormalities (Goldberg). Beside being safe, physical training during hemodialysis is said to contribute to better blood pressure control )Painter 1986). Though dialysis patients may have less tolerance toward these exercise regimes, this may be linked to their physical inactivity – a kind of inescapable circular logic (Johansen 2000, Kouidi). Physical inactivity is a significant danger, as hospitalization during initiation of hemodialysis can lead to muscle cramps and hypotension (Agraharkar). However, physical exercise does not limit other symptoms of renal failure (DePaul). Separately, one study found a possible cause for muscle atrophy in impaired extrarenal K+ regulation; their conclusion was that disturbed K+ regulation contributed to early muscle fatigue during exercise, causing reduced exercise performance (Sangkabutra). Implicated in many of these explanations is nutritional status, a factor separate from dialysis effects.

3) Hearing: Decreased hearing has been linked to the usage of degrading membranes in old dialyzers (Hutter). As a common enough symptom of uremia, dialysis itself does not seem to cause or aggravate hearing loss as the deficits seems to be caused by the pre-existing renal disease (Ozturan, Henrich).

VII. Taste Buds

An interesting sidebar, quite probably related to toxin level and neural dysfunction, is the occurrence of lower numbers of taste buds in renal patients and associated higher recognition thresholds. One significant reason for this has been linked with malnutrition, a common secondary condition in kidney failure (Ohara). Protein-deficient rats were found to have degenerated filiform papillae and imperforated taste pores within the fungiform papillae. The imperforation of the taste pore prevents taste cell communication with the nerve, and thus taste dysfunction could be made possible. As well, lack of protein can ostensibly disrupt the normal cell cycle, preventing regeneration and growth of the taste bud cells. However, one study found no immunohistochemical differences between controls and renal patients (Astback); a lack of taste bud cell growth would presumably retard developments of neurochemical markers and other structural comparisons.


Decreased Chemosensory Function in Renal Disease
Byron Kho and Richard Doty
University of Pennsylvania Smell and Taste Center

Abstract: Despite dialysis and drug therapy, various neurological and physiologic effects are still symptomatic in renal disease patients. While the effects on other motor and sensory systems vary in intensity between no damage to total loss of ability, it is well documented that olfactory and gustatory ability generally decreases, even in cases with low levels of kidney impairment. This review examines the current literature to address the extent of possible damage to chemosensory function in renal disease patients, explore possible explanations of causation, and evaluate possible influences and associations, including neural complications, toxin levels and nutrient intake.

Introduction

Significant decreases in chemosensory function have been documented in patients with chronic renal failure (CRF) and other renal conditions.1-5, 9-14 These patients frequently demonstrate poor nutritional state, increasing the significance of proper diet control within the treatment regimen. Common sense dictates that a decreased ability to smell and taste will negatively affect nutritional habits. As up to 70% of CRF patients complain of decreased taste and enjoyment of their food, it is surprising that the association between CRF and chemosensory deficits has not been more widely researched.6 While the effects on other motor and sensory systems tends to vary in intensity between no damage and total loss of ability 7,8, chemosensory function is generally worse in comparison with controls, even during low levels of kidney impairment.4, 5, 9, 14 Despite these findings, there is still controversy over the mechanism by which these effects are produced, and over the contradictory conclusions of current literature regarding chemosensory acuity and discrimination ability. The present paper seeks to resolve these issues by reviewing the current literature and presenting a general consensus and evaluation of the data regarding the nature of chemosensory damage in renal disease, its mechanisms, influences and associations.

Renal Function and Dysfunction

Renal dysfunction appears in an acute or reversible form, or as CRF, which involves the destruction of nephrons and an inevitable decrease in kidney function. As the kidney controls major regulatory functions within the body, its damage or failure may cause a decreased ability to clear out toxic end products of metabolism from the blood, including urea, creatinine and uric acid, and prevent the proper regulation of inorganic salts. Normally, the kidney supports such functions by exercising control over electrolyte composition and volume or urine, and is assisted by approximately 20% of cardiac output. In the event of damage, patients will be unable to normally dilute and concentrate fluid, reducing the amount of urine produced and increasing toxin levels. A key danger is the continued heightened presence of urea, which may cause uremia, a common condition in CRF. This condition is frequently terminal and induces many nervous complications including impaired mental capacities, generalized weakness, sexual dysfunction and peripheral neuropathies.9, 10 It has been suspected that long-term nervous damage caused by uremia may be at least partially responsible for chemosensory deficiencies.

To reduce toxin levels, treatment regimens may include protein intake restrictions and renal replacement therapies. Reduction of protein intake limits the creation of protein metabolism products, like urea, and eases certain symptoms of uremia. Renal replacement therapies substitute for the normal function of the kidney through renal transplant, or the usage of an external mechanical kidney. This is available in the form of continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD), with HD being the most common approach. However, despite treatment, toxin buildup may still occur and cause additional nervous damage by their chronic regenerative presence in the brain.

Olfactory Deficits

In a 1978 study, Schiffman et al. published one of the first papers to conclude that odor discrimination was significantly reduced in HD patients as compared to normal, young controls.1 Using a multi-dimensional scaling technique, they found that these subjects also rated food odors as significantly more unpleasant than did controls. These findings promoted a possible association between negative hedonic response and decreased olfactory function, and implied that olfactory cues may play major roles in gustation and nutrition status during renal disease.

Studies by Conrad and Corwin also concluded that HD subjects demonstrated a significantly reduced ability to recognize and discriminate between smells.2, 3 These studies utilized olfactory recognition and identification tasks, such as the University of Pennsylvania Smell Test, which requires subjects to correctly identify smells from sets of pairs that are designed to cover a wide range of odor qualities. Additionally, they found that post-dialysis subjects seemed to do worse with identification and discrimination tasks, suggesting that dialysis may decrease or not change olfactory ability.

Recent studies have addressed deficiencies in previous research by including larger subject pools, increased age and sex matching and more quantitative tests of odor discrimination. One study, by Griep et al., asked a total of 101 subjects to sniff different concentrations of isoamyl acetate (banana/pear) using a forced choice paradigm to identify the lowest threshold that a smell was identifiable.4 Their data demonstrated that healthy controls as well as renal transplant patients had significantly lower odor thresholds than patients on either CAPD or HD. However, other studies do not entirely confirm this conclusion. Using “Sniffin’ Sticks,” Frasnelli et al. found that 56% of their 64 patients – 49 of whom were on HD – suffered olfactory loss, but only 11% had elevated odor thresholds.5 The majority of the affected instead exhibited reduced odor discrimination and/or odor identification. Vreman et al. found contradictory results, reporting no significant difference in odor thresholds for pyridine between CRF patients and controls.6

Though the available literature on olfactory deficits in renal disease is small, it is generally accepted that there are deficits in olfactory ability. It is inconclusive as to whether or not the deficit primarily affects the odor identification or discrimination abilities, or odor thresholds, as the data is often contradictory. All these studies utilized patient pools which excluded subjects with cognitive deficits. Even so, psychological tests including the Mini-Mental State Examination and Trail-Making Tests did not necessarily correlate with all or part of the data, undermining the reliability of their conclusions. Thus, one can conclude little beyond the fact that such a chemosensory deficit may occur.

Since it is accepted that olfactory loss affects nutrition, the possibility of such deficits during renal disease should be taken seriously.19 In general, loss of smell seems to lower enjoyment of food, influence patients to alter eating patterns and decreases appetite. However, nutritional status does remain similar to controls, even in anosmic (total loss of ability to smell) patients.20, 21

Gustatory Deficits

A much wider literature is available concerning gustatory loss in renal disease, possibly because of its seemingly more direct association with dietary intake and nutritional status. This is strange, considering that complaints of taste loss are typically reflective of loss of smell function, rather than taste function.23

Decreased nutrition and persistent metallic taste in the mouth are common symptoms of renal failure. Atkin-Thor et al. reported that this metallic taste could also be associated with food. This form of hypogeusia (impaired taste perception) may decrease hedonic perception of food and lead to decreased motivation to eat.

Other gustatory disturbances include a general reduced taste acuity, found in uremic and dialysis patients alike. More specifically, raised taste thresholds have been demonstrated for all the primary tastants in renal patients, as compared to normal, young controls. Additionally, Burge et al. reported in their 1979 paper that though all tastants were affected, sour and sweet taste ability were more seriously affected than bitter or salty. However, several studies found alternate conclusions: namely, that bitter and salty taste were most affected. All studies utilized similar taste tests, requiring whole-mouth rinse between samples of solutions representing each taste (salt/NaCl, sugar/sucrose, sour/citric acid, bitter/quinine) and random inclusions of water to assure data accuracy.

Despite the contradictory nature of the data, it is accepted that such deficits occur, and that dialysis often improves taste acuity. Burge et al. found that sweet and sour taste thresholds decreased significantly following dialysis, though they still remained higher compared to controls. Fornari and Avram found that only sweet taste lowered after dialysis. Other studies report an increased sensitivity and preference for salt after dialysis, though Leshem and Rudoy argue that these values return to pre-dialysis levels 24 hours after treatments.

A 1984 paper by Burge and colleagues argued that age may play a part in taste recognition. They suggested that taste recognition thresholds for sour and sweet increase as renal function declines. By their hypothesis, children with renal disease should demonstrate the highest functioning taste capability. A study by Shapera et al. seems to confirm this: they found no difference in taste thresholds between normal children and children with renal disease. This is not unexpected, as normal taste sensitivity itself has been shown to change with age. This association with age seems to continue even with or despite dialysis treatment. Ciechanover et al. found that patients younger than 55 years tended to improve in the recognition of sour and bitter after dialysis, whereas older patients showed little to no change. However, some conclusions may be suspect because taste loss can still occur without concurrent changes in threshold levels, as Schiffman has shown in studies with the elderly.

As previously mentioned, lowered taste acuity does affect nutritional status. Mattes and Cowart found that dysgeusic patients generally found decreased enjoyment in food and had to alter their eating patterns and usage of seasonings. Though their mean nutrient intake was normal, about 20% experienced a change in body weight. Renal patients frequently experience anorexia, suggesting that they too are dysgeusic.

Causation and Refutations

One such theory posited that low nutrient availability due to dialysis removal could limit receptor cell turnover rate and lead to that result (Schiffman 1978), but as the problem occurs independent of dialysis treatment, this is unlikely. In fact, dialysis itself may not change or lead to a lowering of olfactory ability (Conrad 1987, Corwin 1989). Instead, recent studies have concluded that these olfactory impairments – and to a lesser extent, gustatory impairments – are related to the degree of accumulation of uremic toxins (Griep 1997). Even if dialysis constantly removes toxins, chronic exposure may limit smell and taste ability and could take weeks recover, which could explain non-recovery of these abilities after dialysis treatments. This theory is lent credence by the fact that kidney transplantation returns olfactory and gustatory levels to normal. Conrad et al. have proposed that neuropathies caused by toxin damage may cause damage to the cranial nerves, which promote smell and taste information to the brain; additionally, it may cause subtle changes in brain processing that can impair tests of olfactory discrimination and identification (Conrad 1987).

However, dual activation of the olfactory and trigeminal receptor system may be responsible for this difference. One study showed no difference in olfactory perceptions with activation of the trigeminal system (Vreman); another used a substance with minimal trigeminal effect and showed significant difference (Griep), supporting a deficiency in the olfactory receptor system in uremic patients. The trigeminal system is only activated by certain averse stimuli like ammonia, independent of the main olfactory system.

What is responsible for this lowered odor perception, then? Low nutrient availability due to dialysis removal could limit receptor cell turnover rate and lead to that result (Schiffman), but as the problem occurs independent of dialysis treatment, this is unlikely. Most likely, it has to do with levels of toxins in the blood. Interestingly enough, transplantation returns olfaction and gustation to normal (Griep). This shows that materials in the blood being filtered – or not being filtered – are most probably responsible for the lowering of smell and taste perception. It has been proposed that urea might be one factor. The idea is that the effect of urea may be long-term, as urea removal by hemodialysis – or peritoneal dialysis – does not improve olfaction. Possibly, chronic exposure to urea limits smell ability and could take weeks to recover from, to explain the non-recovery after hemodialysis.

Another related factor are the neuropathies present in kidney damage and uremia (Fraser 1988). Typical effects include a slowing of conduction in the sensory nerves by demyelination and axonal degeneration, as well as problems with higher brain function. Uremic rats have shown altered or damaged calcium pumps (Fraser 1985), and as these mediate NT release in the CNS, this may affect information processing. Damage to other pumps supplying energy to the axons will result in neuron degeneration. Also, damage to the blood brain barrier allows differing amino acid concentrations in the cerebrospinal fluid and blood, which can cause synthesis of defective neurotransmitters (Cantaro). These neuropathies can be recovered from using dialysis, albeit very slowly, and full recovery is possible after transplantation (Burn) – which follows the course of olfactory and gustatory recovery. The direct effect of neuropathies on smell and taste include damage to the cranial nerves, which promote smell and taste information to the brain, and possibly subtle changes in brain processing that can impair tests of olfactory discrimination and identification (Conrad). For example, changes to the amygdala and hippocampus can change detection and response to averse stimuli. Zinc, associated with several of these neuropathies, occurs only in low amounts during renal failure; its restoration improves caloric intake and shows recovery of both neuronal function and taste acuity (Sprenger, Vreman).


Influences of Kidney Disease and Dialysis on Chemosensory Function

Download file.


Mapping Human Taste Thresholds

Download file.


PAX Genes and Cancer

Download file.


CML, Gleevec, and Targeted Drugs

Every year, 30,000 people in the United States are diagnosed with chronic myelogenous leukemia, or CML. CML targets the white blood cells known as myeloid cells that are manufactured in the bone marrow and causes them to grow abnormally. Normally, cells will divide and later self-destruct in an orderly manner as regulated by a cell cycle and checkpoint system; however, in cancer, the cell’s genetic blueprints are damaged, causing its cell division mechanisms to be turned on indefinitely and preventing the cell from maturing properly, thus not allowing the cells to die. The rapidly dividing cells fill the bone marrow and spread around the body through the lymphatic and circulatory systems, preventing the manufacture of healthy cells and exposing the body to increased risk of infection and bruising. External symptoms include anemia, fatigue, repeated infections, enlarged spleen and unusual bleeding. Though this disease is usually fatal, treatments have been found that successfully reverss the effects of the cancer by aiming at the mechanisms by which CML perpetuates itself, most notably imanitib mesylate or Gleevec.

Current treatments for CML include transplantation and interferon therapy, which attempt to restart the immune system, and radiation therapy and chemotherapy, which attempts to kill the rapidly dividing cancerous cells with radiation and chemicals respectively. Chemotherapy works by inhibiting DNA synthesis and thus killing all cells that need to rapidly divide, including both cancer cells and normally rapidly dividing cells. The principle behind chemotherapy is that the cancer will have been defeated when all the cancer cells are killed, and so drugs of high toxicity are used to achieve that end. However, these drugs can also cause further cancers, and are used in combination with drugs of low toxicity to contain the damage. Even though these treatments do extend the life of a cancer patient, they are not ultimately very effective; current drug research raises the effectiveness of newly designed drugs by more specifically targeting them to the specific mechanisms by which cancer is caused.

The first step to identifying the oncogenic mechanism was taken in 1961, when a study linked CML with the presence of a chromosomal aberration known as the Philadelphia (Ph) chromosome. The fact that 90% of all CML sufferers today have this chromosome was strong evidence of a genetic link to CML. At first, it was believed that the Ph chromosome was a mere marker of malignancy, but further study showed that the aberrant chromosome did actually have a causative role in cancer.

Initial analysis was not able to pinpoint the exact nature of the aberration; later studies concluded that it was actually a translocation – a joining of segments from different chromosomes. This chromosome, as well as any other chromosome, contains genes coding for proteins that are needed to maintain body functions. Specifically, the genes implicated in the translocation were the c-ABL locus on chromosome 9 that codes for a tyrosine kinase, and the BCR locus, or breakpoint cluster region, on chromosome 22. Tyrosine kinases are a class of enzyme that phosphorylates, or adds phosphate groups to, the amino acid tyrosine. ABL, with one base mutation, can turn into an oncogene, extending signaling indefinitely. The BCR-ABL gene was further implicated in cancer by the discovery that its products included P210, an active protein associated with CML. Other scientists observed that in the rare case of CML patients not having the Philadelphia chromosome, the BCR-ABL fusion gene was still present, though on a normal chromosome 22. In the search for a mechanism to cancer, the first step had been discovered and a possible drug target identified in the BCR-ABL gene.

To further define the specific target area of an anti-cancer drug, scientists delved further into the mechanisms by which BCR-ABL can initiate the process leading to cancer. These studies were able to define a participatory link between the BCR-ABL protein complex and the Ras signaling pathway, a molecular communication conduit for cell division. One study found that BCR-ABL regulates c-RAF-1, a downstream effector of the Ras pathway. Another study found that BCR-ABL was able to upregulate the Ras pathway through an adaptor protein called GRB-2, an anchorage molecule within the cell scaffolding. Upregulation of the Ras pathway effectually increases signal traffic and allows heightened levels of unregulated growth for an indefinite time. These findings were very important in establishing a linkage between the BCR-ABL protein and the direct cause of an important symptom of cancer.

Another finding strengthening the importance of BCR-ABL in the oncogenic mechanism was the discovery of a linkage to Bcl-2, a gene intimately involved with apoptosis. Normally, when cells are damaged, Bcl-2 will signal other proteins to start apoptosis, but heightened levels of Bcl-2 were preventing cell apoptosis in certain cancers, which were also associated with chromosomal translocations. Apoptosis was quickly reached in the absence of a normal growth factor, but within cells containing both BCR-ABL and Bcl-2, cell division continued in defiance of apoptosis. Scientists were then able to conclude that Bcl-2 was an important mediator in the BCR-ABL pathway to cancer.

In the search for a successful treatment, scientists now had a suitable target: BCR-ABL. Not only are its protein products a positive marker of cancer, it is linked to the specific symptoms of cancer – unregulated cell division and inactive apoptotic mechanisms. A vaccine, created by the Memorial Sloan-Kettering Cancer Center, uses the BCR-ABL fusion gene as a target to stimulate patient immunity to their cancer cells and to the proteins that cause the disease. Other such drugs designed around this target work under the assumption that a blockage of BCR-ABL activity will reverse the cancer phenotype; these include CGP 57148 and imanitib mesylate. The blockage of activity is achieved by blocking the ATP binding site of the kinase, thus removing the source of the phosphate groups which ABL uses in its function as a tyrosine kinase.

Imanitib mesylate, otherwise known as STI 571 or Gleevec, is currently the most active and practical agent yet discovered against CML. Though allogeneic stem cell transplantation can potentially cure CML, it is impractical because of the difficulty in matching donors to those in need. Studies have shown that it eradicates CML cell proliferation in mice and inhibits the proliferation of CML cells in the lab, which are derived from cell lines and actual CML patients. Toxicology studies have determined that the drug is safe for human trials; clinical trials returned sufficient success rates in treating Ph+ CML. In 2001, imanitib mesylate was finally approved for use in the US by the FDA under the trade name Gleevec. A February 2002 paper in the New England Journal of Medicine said that 95% of treated CML sufferers are still alive after 18 months, and 60% of patients achieved a major cytogenetic response – less than 1% presence of Ph chromosome in the cells of the bone marrow. A later study in the same journal found Gleevec to be 9 times more likely to stimulate a full cytogenetic response than more traditional drug treatments.

For those many Americans who suffer from CML every year, the prognosis can be much improved from use of such effective drugs in combination with other treatments. Imanitib mesylate or Gleevec, the most potent example, was discovered through research into the mechanisms by which cancer spreads – particularly, the BCR-ABL gene as a major focus. Future research could possibly reveal better treatments using increasingly more potent knowledge of the oncogenic mechanism.


Causation of Criminality: Genetic and Environmental Influences

Download file.


A Discussion on Sexual Selection

Download file.


Indicators: Their Utility in Male Trait Evolution

Download file.