Timothy W. Meyer Thomas H. Hostetter
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Solutes Cleared by the Kidney and Retained in Uremia, 1681 |
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Individual Uremic Solutes, 1682 |
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Solute Removal by Different Forms of Renal Replacement Therapy, 1687 |
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Effects of Diet and Gastrointestinal Function, 1688 |
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Solute Excretion by Tubular Transport Systems, 1688 |
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Metabolic Effects of Uremia, 1688 |
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Oxidant Stress and the Modification of Protein Structure, 1688 |
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Resting Energy Expenditure, 1689 |
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Carbohydrate Metabolism, 1689 |
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Amino Acid Metabolism, 1690 |
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Lipid Metabolism, 1690 |
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Signs and Symptoms of Uremia, 1690 |
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Well-Being and Physical Function, 1691 |
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Neurologic Function, 1691 |
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Appetite, Taste, and Smell, 1691 |
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Cellular Functions, 1692 |
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Why Is Glomerular Filtration Rate So Large?, 1692 |
The word uremic is generally used to describe those ill effects of renal failure that we cannot yet explain. Hypertension due to volume overload, tetany due to hypocalcemia, and anemia due to erythropoietin deficiency were once considered uremic signs but were removed from this category as their causes were discovered. In the present state of knowledge, uremia may thus be defined as the illness that would remain if the extracellular volume and inorganic ion concentrations were kept normal and the known renal synthetic products were replaced in patients without kidneys ( Table 47-1 ).
Some features of uremia, thus defined, could reflect the lack of unidentified renal synthetic products. But we presume that uremic illness is due largely to the accumulation of organic waste products that are normally cleared by the kidneys. In general, the study of renal organic waste removal has lagged far behind the study of inorganic ion excretion. A major problem is the multiplicity of waste solutes. The most comprehensive review to date, prepared by the European Uremic Toxin Work Group (EUTox),[1] lists more than one hundred uremic solutes and provides references to chromatographic studies describing others. With so many substances to study, it is hard to establish which ones are toxic. Bergstrom[2] suggested criteria for identifying uremic toxins that are analogous to Koch's postulates for identifying infectious agents. According to these criteria, a uremic toxin must have a known chemical structure and
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Its plasma and/or tissue concentrations should be higher in uremic patients than in normal people. |
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The high concentrations should be related to specific uremic symptoms that are ameliorated when the concentration is reduced. |
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The effects observed in uremic patients should be replicated by raising the solute concentration to uremic levels in normal people, experimental animals, or in vitro systems. |
No uremic solute has so far been shown to satisfy these criteria. The likelihood that studies of individual solutes will yield negative results has discouraged research. Most uremic solutes are probably not toxic, and those that are toxic may exert their ill effects only when administered in combination.
The difficulty imposed by the multiplicity of solutes is compounded by the multiplicity of ill effects encountered in uremia. Investigators of uremic toxicity thus face the daunting task of matching a solute or group of solutes to an appropriate end point. Many of the effects of uremia are hard to quantify, which makes the problem all the more difficult. This is particularly true of major uremic symptoms such as fatigue, anorexia, and diminished mental acuity.
A further major problem encountered in clinical studies of uremia is distinguishing the effects of uremia from those of related conditions. Paradoxically, the development of dialysis has made uremia harder to study. The severity of the classic uremic symptoms is much attenuated and patients now suffer from a new illness, which Depner[3] has aptly named the residual syndrome, comprising partially treated uremia and the side effects of dialysis. In most patients, features of the residual syndrome are further combined with the effects of age and of systemic diseases responsible for the loss of kidney function. Disturbance of inorganic ion metabolism including acidemia and hyperphosphatemia, though excluded from our definition of uremia, also undoubtedly contribute to illness in dialysis patients. Given these difficulties, it is not surprising that knowledge of the accumulation of uremic solutes, as summarized later, is accompanied by limited information regarding their toxicity. In some cases, uremic abnormalities have been reproduced by the transfer of uremic serum or plasma to normal animals or cells ( Table 47-2 ), but the role of particular solutes in causing these abnormalities remains uncertain.
TABLE 47-1 -- Symptoms and Signs of Uremia
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Neural and muscular |
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Endocrine and metabolic |
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Other |
TABLE 47-2 -- Uremic Abnormalities Transferable with Uremic Serum or Plasma
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Inhibition of sodium-potassium ATPase |
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Inhibition of platelet function |
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Leukocyte dysfunction |
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Loss of erythrocyte membrane lipid asymmetry |
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Insulin resistance |
SOLUTES CLEARED BY THE KIDNEY AND RETAINED IN UREMIA
The long list of solutes retained in uremia has been assembled in two ways. Initially, biochemists would find a substance in the urine and then look for it in the blood of uremic patients. Several dozen uremic solutes were identified in this way as the biochemical pathways of intermediary metabolism were worked out. Beginning about 1970, improved analytic techniques including gas chromatography, mass spectroscopy, and high-performance liquid chromatography were used to identify numerous additional uremic solutes.[4] Often, the new methods identified compounds that were structurally related to a previously known uremic solute but present in lower concentrations. For example, the tryptophan degradation product indoxyl sulfate was identified in the urine in the late 19th century and shown to accumulate in the blood of uremic patients in 1911. By 1970, several other indoles had been shown to accumulate in uremia and the subsequent application of high performance liquid chromatography led to the identification of additional substances.
Recent technical advances, including the development of proteomic and metabolomic screening techniques, will undoubtedly lengthen the list of uremic solutes. But the problem of determining which solutes are toxic remains. In general, the compounds that are present in the highest concentrations, and were therefore identified first, have been studied most. Plasma concentrations of several compounds have been shown to correlate more closely with uremic symptoms, and in particular with altered mental function, than concentrations of urea or creatinine. In some cases, these compounds have been shown to accumulate in the cerebrospinal fluid (CSF) consistent with their proposed effect on the brain. But experiments showing that uremic signs and symptoms can be replicated by raising solute levels in normal people or animals to equal those observed in uremic patients are lacking. When attempted, such experiments have generally shown that the solutes being studied are more toxic than urea but that the levels required to produce toxic effects are higher than those measured in patients. Because so little is known about their toxicity, the discussion of uremic solutes is usually organized on the basis of their structure and not their contribution to disease.
Individual Uremic Solutes
Urea
Urea is quantitatively the most important solute excreted by the kidney, and levels rise higher than those of any other solute when the kidney fails. But early studies indicated that urea causes only a minor part of uremic illness. [5] [6] [7] In the most often cited of these studies, Johnson and co-workers[6] dialyzed three patients with renal failure against bath solutions containing urea. They found that initiation of hemodialysis improved uremic symptoms including weakness, fetor, and gastrointestinal upset even when the blood urea nitrogen (BUN) was maintained at approximately 90 mg/dL. In patients already on dialysis, increasing the BUN to 140 mg/dL did not cause recurrence of uremic symptoms. Increasing the BUN above 140 mg/dL caused nausea and headaches, and increasing the BUN above 180 mg/dL caused weakness and lethargy. But symptoms in dialyzed patients whose BUN values were increased to these levels were believed to be much less severe than symptoms in undialyzed patients with similar BUN values. Studies in patients without renal failure further suggest that urea by itself does not cause uremia. Uremic symptoms have not been observed in patients whose BUN levels are maintained at approximately 60 mg/dL by high protein intake or increased tubular urea absorption. [8] [9] [10]
The finding that uremia is not replicated by an isolated elevation of the urea level does not mean that urea has no toxic effects.[11] The full expression of uremia may require accumulation of urea plus other solutes. Johnson and co-workers[6] noted that patients dialyzed against solutions of urea exhibited increased bleeding, and subsequent studies have suggested that urea causes bleeding by promoting synthesis of guanidinosuccinic acid, which in turn, impairs platelet function. [12] [13] Increased urea levels may cause other ill effects by promoting protein carbamylation.[14] Isocyanate, which forms spontaneously at a rate proportional to the urea concentration, combines irreversibly with unprotected amino groups to form carbamylated proteins ( Fig. 47-1 ). This process can be considered analogous to the formation of glycated proteins in diabetes, and measurement of hemoglobin carbamylation provides an index of the time-averaged urea concentration.[15] Isocyanate can also combine reversibly with OH and SH groups of amino acids, and the various isocyanate-induced alterations in structure could impair protein function.
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FIGURE 47-1 The generation of potential uremic toxins. The substances in the right column of each panel are metabolites that are normally excreted by the kidney and that, therefore, accumulate in the extracellular fluid when kidney function is lost. The left column shows the substances from which these potential “uremic toxins” are derived. In some cases, the biochemical derivation of the potential toxins is uncertain. For instance, it is not known what fraction of the dimethylamine normally excreted is derived from choline and the source of 3-carboxy-4-methyl-5-prophy-2-furanpropanoic acid (CMPF) is obscure. See text for details. |
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A further potential consequence of increased urea levels is increased ammonia production. Each day, colonic bacteria transform a portion of the body urea pool to ammonia, which is then taken up by the liver and either converted back to urea or incorporated into amino acids. [16] [17] Surprisingly, the flux through this pathway appears not to increase as urea levels rise in patients with renal failure and gut ammonia synthesis and blood ammonia levels remain normal.[17] Recent studies, however, have found that breath ammonia levels are markedly elevated in hemodialysis patients and fall during treatment. [18] [19] Why breath ammonia levels are elevated while blood ammonia levels remain normal is unexplained.
d-Amino Acids
In comparison to urea, we know much less about most other potential uremic toxins. The d-amino acids exemplify this problem. Aggregate plasma levels of d-amino acids increase as kidney function declines. [20] [21] But the source, clearance, and toxicity of the d-amino acids found in the plasma are not well defined. Recent studies have shown that d-amino acids can be synthesized by mammalian cells as well as derived from food and produced by colonic bacteria.[22] Circulating d-amino acids are filtered by the glomerulus and, then in varying proportion, reabsorbed intact, degraded by d-amino acid oxidase (DAO) or d-aspartic acid oxidase in the proximal straight tubule, or excreted unaltered in the urine. [23] [24] The liver can also clear d-amino acids, and the relative importance of renal and hepatic clearance is not known. Aggregate d-amino acid levels have been found to increase almost in proportion to the serum creatinine in renal failure, suggesting that renal clearance predominates. [20] [25] [26] But levels of individual d-amino acids measured so far, including d-serine, increase less than the creatinine. [25] [26] This discrepancy remains unexplained. It is tempting to speculate that d-amino acids are cleared rapidly from the ECF because they have toxic effects. In addition, it has long been presumed that high levels of d-amino acids could impair protein synthesis or function.[22] d-Amino acid accumulation could also interfere with the recently identified effects of endogenous d-serine and d-alanine on neuronal function.[27] However, no major ill effects of d-amino acid accumulation have been observed in DAO-deficient mice, which have higher d-amino acid levels than humans with renal insufficiency. [28] [29] In addition, exogenous d-amino acids have so far been shown to be toxic only when administered in large quantities. [28] [30]
Peptides and Proteins
The kidney clears circulating di- and tripeptides, which may make up a significant portion of the extracellular amino acid pool.[31] Filtered di- and tripeptides can be broken down by brush border peptidases and reabsorbed as amino acids or reabsorbed by a brush border peptide transporter and then hydrolyzed within proximal tubule cells.[32] Peritubular uptake, again followed by hydrolysis to amino acids, makes the renal clearance of many peptides greater than the glomerular filtration rate (GFR). [31] [33] However, small peptides are also taken up by other organs and generally do not accumulate in renal failure. Peptides containing altered amino acids, which are normally cleared by the kidney, may be an exception to this rule.[33]
The kidney plays a proportionally greater role in the clearance of larger peptides. Proteins with molecular weight 10 to 20 kD such as β2-microglobulin and cystatin C are normally filtered by the glomerulus and then endocytosed and hydrolyzed in the lysozomes of proximal tubular cells. [34] [35] Their plasma levels, therefore, rise in close proportion to the plasma creatinine as the kidney fails. Indeed, the plasma concentration of cystatin C, which is released at a near-constant rate by nucleated cells, may provide a better measure of the GFR than the concentration of creatinine. The role of the kidney in the removal of peptides with molecular weight between 500 and 10 kD is less well defined. Peptides in this range are also filtered by the glomerulus and then either hydrolyzed by brush border peptidases or endocytosed depending on their size and structure. Biologically active peptides such as insulin may also be cleared by peritubular uptake. Studies in patients with inherited dysfunction of proximal tubular endocytosis suggest that the normal kidney clears approximately 350 mg/day of peptides with molecular weight 5 to 10 kD from the circulation.[36] But the relative importance of renal to extrarenal clearance has not been defined for most substances in this size range. The extent to which circulating levels of such peptides are increased in renal failure is, therefore, unpredictable. Even less is known about the kidneys' contribution to the clearance of peptides in the range of 500 D to 5 kD. But the summed level of peptides and small protein concentrations in the plasma of uremic patients has been estimated to be approximately 50 mg/L.[37]
Whereas the aggregate peptide levels in renal failure remain ill defined, we have some knowledge of individual retained substances. These include protein degradation products like the C-terminal fragments of parathyroid hormone (PTH) as well as intact small proteins like cystatin C. The middle molecule hypothesis stimulated early workers to isolate and sequence a few peptides from uremic serum. Proteomic techniques are now being applied and will, hopefully, yield a fuller picture. [38] [39] One study suggests that the bulk of retained peptides with molecular weight 500 D to 5 kD are fibrinogen fragments.[39] Another study has identified more than 1000 peptides with molecular weight from 800 D to 10 kD in the plasma of dialysis patients.[40] The central question, of course, is whether any of these substances are toxic. It has been widely speculated that retained peptides can cause inappropriate activation of various hormone or cytokine receptors. For example, retained complement protein D (Mol wt 24 kD) could contribute to systemic inflammation and excess vascular disease in dialysis patients.[41] Such hypotheses remain largely unproved, however, and β2-microglobulin is the only retained peptide that has been convincingly shown to cause disease.
Guanidines
Among the compounds most frequently considered uremic toxins are guanidines, which, like urea, are derived from arginine (see Fig. 47-1 ). [42] [43] One group of guanidines that accumulates in uremia includes creatinine and its breakdown products. Creatinine is produced by nonenzymatic degradation of creatine, which, in turn, is made from guanidinoacetic acid (GAA).[44] Creatinine itself appears not to be toxic, and levels have been increased transiently to more than 100 mg/dL in subjects undergoing clearance studies. Interest has been focused rather on the potential toxicity of various creatinine metabolites, including particularly creatol and methylguanidine. [45] [46] The production of these substances increases as creatinine levels rise and may be stimulated by increased levels of intracellular oxidants. [43] [44] [45] Methylguanidine is also produced by colonic bacteria, and its production may be increased by increasing the dietary intake of protein or creatinine.[47] Another guanidine that has attracted interest in guanidinosuccinic acid (GSA), which is formed not from creatinine but from the urea cycle intermediate arginosuccinate. [48] [49] Rising urea levels impede the conversion of arginosuccinate to urea and increase the production of GSA. The production of GSA thus depends on dietary protein intake as well as on renal function and may in renal insufficiency also be stimulated by increased levels of intracellular oxidants. [49] [50]
Creatol, methylguanidine, and GSA share the interesting property that their plasma levels rise out of proportion to urea and creatinine levels as the GFR falls. This is because they are cleared largely by glomerular filtration and their production increases as creatinine and urea levels rise. [43] [44] [45] In addition, large volumes of distribution combined with restricted intercompartmental diffusion may limit the removal of creatol, methylguanidine, and GSA by hemodialysis.[42] In patients receiving conventional intermittent treatment, these compounds therefore exhibit the highest concentrations relative to normal of the known uremic solutes.[1] The finding that they are present in relatively high concentrations does not, of course, prove that they are toxic. But the evidence for the toxicity of various guanidines, although incomplete, is stronger than that for most other solutes. Administration of methylguanidine aggravates uremic symptoms in dogs, whereas GSA contributes to uremic platelet dysfunction and a number of guanidines impair neutrophil function. [12] [51] [52] In addition, various guanidines have been shown to accumulate in the brain and CSF in uremia and may contribute to central nervous system (CNS) dysfunction.[53]
The methylated arginines asymmetrical dimethyl arginine (ADMA) and symmetrical dimethyl arginine (SDMA) also accumulate in renal failure (see Fig. 47-1 ). But their metabolism is quite different from that of the other “uremic” guanidines. ADMA and SDMA are formed by methylation of arginine residues in nuclear proteins and released when these proteins are degraded. Interest has focused largely on ADMA because it inhibits nitric oxide synthesis, whereas SDMA is relatively inactive. [54] [55] The kidney clears ADMA at a rate approximating the creatinine clearance, but the majority of plasma ADMA is taken up and degraded intracellularly at other sites.[54] The increase in ADMA levels observed in patients with renal insufficiency is, therefore, generally attributed to a reduction in extrarenal clearance, as an increase in their production has not been observed. The mechanism responsible for reducing the extrarenal clearance of ADMA in renal disease is not known. But it is remarkable that ADMA levels may rise to approximately twice normal very early in the course of renal disease and then do not increase much further as patients advance to end-stage renal disease (ESRD).[56] Increases in ADMA levels, although modest in proportion to increases in the levels of other uremic solutes, have been associated with accelerated progression of renal injury and an increased risk for cardiovascular disease and death in patients with renal disease.[57]
Phenols and Other Aromatic Compounds
Phenols are compounds having one or more hydroxyl groups attached to a benzene ring. In discussions of uremia, phenols are usually considered together with other aromatic compounds such as hippurates, and the term phenols is sometimes used loosely to include these other substances. The aromatic compounds normally found in the ECF are for the most part derived either from the amino acids tyrosine and phenylalanine or from aromatic compounds contained in vegetable foods. Medications provide an additional source in patients. The compounds in the ECF are mostly metabolites, derived from their parent compounds by a combination of methylation, dehydroxylation, oxidation, reduction, and/or conjugation. Many of these reactions take place in colonic bacteria. The final step, which is usually conjugation with sulfate, glucuronic acid, or an amino acid, may take place in the liver, the intestinal wall, or to a lesser extent, the kidney. [58] [59] In general, conjugation tends to make the aromatic compounds at once less toxic and more polar, which facilitates their excretion by various organic ion transport systems.
The metabolic processes described previously produce a bewildering array of aromatic compounds that are normally excreted in either the urine or the feces. The aggregate urinary excretion of aromatics is on the order of 1000 mg/day and varies widely with the diet. The compounds normally excreted by the kidney accumulate in uremia and contribute to the elevation of the anion gap, because the majority of aromatic conjugates are negatively charged.[60]Levels of individual compounds in uremic patients range from barely detectable up to 500 μM. [1] [61] [62] [63] The relatively few compounds that have been studied extensively, including the examples described later, are among those found in the highest concentrations. However, there is no reason to think that the compounds found in the highest concentrations are the most toxic. Interest in the contribution of phenols and other aromatic compounds to uremic toxicity has been encouraged by reports that uremic symptoms are better correlated with levels of these compounds than with levels of other solutes. [7] [64] [65] [66] However, evidence so far obtained for the toxicity of individual aromatic compounds is not strong.
The most extensively studied aromatic uremic solute is hippurate (see Fig. 47-1 ). Because it is the aromatic waste compound normally excreted in the largest quantity, its free level rises higher than those of other aromatic solutes in the plasma of uremic patients. Hippurate is the glycine conjugate of benzoate, which is derived largely from vegetable foods with only a small amount formed endogenously from the amino acid phenylalanine. [67] [68] Diet, therefore, determines hippurate production, and hippurate excretion in aboriginal people eating vegetable diets may exceed hippurate excretion in people from industrialized nations by manyfold.[69] In people with normal kidneys, active tubular secretion keeps hippurate levels much lower than they would be if hippurate were cleared solely by glomerular filtration. Hippurate, however, is not toxic. Hippurate levels in normal humans can be increased to equal those of uremic patients without apparent ill effect.[70] In addition, increasing hippurate levels by benzoate feeding in patients with renal failure does not aggravate uremic symptoms.[71]
Another extensively studied aromatic compound is p-cresol. In contrast to hippurate, which is derived from aromatic compounds in plants, p-cresol is formed by the action of colonic bacteria on tyrosine and phenylalanine. The portion of amino acids that escapes absorption in the small intestine may be increased in uremic patients, leading to increased production of p-cresol and other bacterial metabolites.[72] P-cresol binds avidly to serum albumin, and the effect of different renal replacement therapies on albumin-bound solutes has often been tested by measuring p-cresol levels. [73] [74] Unconjugated p-cresol is toxic.[75] But p-cresol circulates almost exclusively as p-cresol sulfate, which is much less toxic, and reports of unconjugated p-cresol in the plasma of uremic patients now appear to have been the result of inadvertent hydrolysis of p-cresol sulfate during the processing of plasma samples. [76] [77] [78]
Other aromatic uremic solutes have been identified in great numbers but studied less extensively. [2] [62] [63] Metabolites of tyrosine and phenylalanine that accumulate in uremia include phenylacetylglutamate, parahydroxyphenylacetic acid, and 3,4-dihydroxybenzoic acid as well as p-cresol. [79] [80] [81] The structural relation of these aromatic amino acid metabolites to neurotransmitters has stimulated interest in their potential role as uremic toxins. So far, 3,4-dihydroxybenzoate has been shown to cause CNS dysfunction in rats, but only at levels higher than those encountered in uremic patients.[80] The work of testing the toxicity of other aromatic uremic solutes is daunting, and little progress has been made.[2]
Indoles and Other Tryptophan Metabolites
Indoles are compounds containing a benzene ring fused to a five-membered nitrogen-containing pyrrole ring (see Fig. 47-1 ). Many similarities are encountered in considering the indoles and phenols in uremia. As with the phenols, some indoles are derived from plant foods and others are produced endogenously. But the endogenous indoles are derived mostly from tryptophan, whereas the phenols are derived from phenylalanine and tyrosine. As with the phenols, minor chemical modifications in various combinations yield a remarkable variety of structures, with more than 600 indoles derived from tryptophan.[82] Those with known physiologic function include the neurotransmitter 5-hydroxytryptamine (serotonin) and melatonin. Other indoles are considered to be waste products and are often conjugated before urinary excretion. These uremic indoles accumulate in the ECF when renal function is reduced.
The most extensively studied of the uremic indoles is indoxyl sulfate, or indican. Indican is produced from tryptophan in a manner reminiscent of the production of p-cresol sulfate from tyrosine and phenylalanine. Gut bacteria convert tryptophan to indole, which is then oxidized to indoxyl and conjugated with sulfate in the liver. There is evidence that indican is toxic in vitro, but early studies of indican infusion failed to replicate uremic symptoms. [7] [83]Like p-cresol sulfate, indican is extensively bound to serum albumin, and recent studies have employed it as a marker of the removal of protein-bound solutes by renal replacement therapies.[74] It has also been suggested that indican is toxic to renal tubular cells and that increasing indican levels accelerate loss of remnant nephrons in kidneys that have been damaged by disease.[84]
Other indoles that accumulate in uremia include indoleacetic acid, indoleacrylic acid, and 5-hydroxyindoleacetic acid. [1] [85] [86] As with the phenols, the indoles are structurally related to potent neuroactive substances, which in the case of the indoles include serotonin and lysergic acid diethylamide (LSD). This structural similarity has stimulated interest in their potential role as neurotoxins, but few uremic indoles have so far been administered to normal animals, and none has convincingly been shown to alter CNS function at the levels encountered in uremic patients.
Only a minor portion of dietary tryptophan is excreted as indoles. Most is metabolized by the kynurinine pathway that allows tryptophan to be converted to glutarate and oxidized or, when necessary, used in the synthesis of nicotinamide. Renal failure causes members of the kynurinine pathway including L-kynurinine and quinolinic acid to accumulate in the plasma. [87] [88] Knowledge that these substances play a physiologic role in the modulation of CNS function has stimulated interest in their possible contribution to uremic toxicity. As usual, however, evidence that they are toxic at the levels encountered in uremic patients has not been obtained.
Aliphatic Amines
The methylamines monomethylamine (MMA), dimethylamine (DMA), and trimethylamine (TMA) are among the simplest compounds that have been considered to be uremic toxins. Early studies identified high levels of DMA and TMA in patients with impaired renal function, and subsequent studies reported a more than 10-fold rise in serum concentrations for both DMA and MMA in people with ESRD compared with controls. [89] [90] However, available data and predictions based on their chemistry suggest the methylamines are poorly removed by dialysis, and limited data suggest that they may even be produced in excess in uremia.
A large volume of distribution may contribute to poor removal of the methylamines by dialysis. These compounds are bases with pKs ranging from 9 to 11. Thus, they exist as positively charged species at physiologic pH. The lower intracellular pH compared with ECF should lead to their preferential intracellular sequestration with volumes of distribution exceeding total body water. Indeed, measurements in experimental animals and humans have confirmed these predictions for DMA and TMA. [91] [92]
Because they circulate as small organic compounds that are not protein bound, these three amines are likely freely filtered. However, because they exist as organic cations, they also have the potential to be secreted by one or another of the family of organic cation transporters.[93] Hence, they may achieve clearances that are, in fact, greater than the GFR. The chemically similar exogenous compound tetraethyl ammonium has long been a prototype test solute for organic cation secretion and is cleared at rates up to (and, in one study, above) the renal plasma flow. [94] [95] Whereas formal renal clearances of MMA, DMA, and TMA are not available, the total metabolic clearances of DMA and TMA by plasma disappearance of labeled compounds in rats approach that of renal plasma flow.[91]
The biochemical pathways leading to MMA, DMA, and TMA are not well delineated. Both the host's mammalian tissues and resident gut flora seem to contribute to the net appearance of these amines. The dietary precursors for MMA, DMA, and TMA include choline and trimethylamine oxide (TMAO). [96] [97] [98] Production of these compounds may actually be increased with uremia owing to overgrowth of intestinal bacteria. [92] [99] Thus, suggestive data support the possibility that, in the patient with ESRD, production may be increased in the face of impaired renal removal.
Incomplete data also implicate the amines as toxic.[100] Their levels were found to correlate better than creatinine with impairment of brain function as manifest by electroencephalography and cognitive testing.[101] Perhaps more telling but less quantitative was the association between falls in amine levels and clinical improvement in myoclonus, asterixis, and mental acuity when nonabsorbable antibio-tics were administered orally even without dialysis and, hence, without change in serum urea or creatinine.[102] This effect was attributed to suppression of the overgrowth of intestinal flora that produces these aliphatic amines. Other toxicities have been assigned to this class of amines as well. MMA may be the most toxic, and its effects include a variety of neural toxicities, hemolysis, and inhibition of lysosomal function.[103] The uremic fetor or fishy breath noted in uremic patients is attributable to TMA.[104]Although the malodor may be of no major consequence in itself, the potentially important and well-described diminutions in taste and smell among these patients may also be related to the amines. More recently, two additional adverse actions have come to light. MMA is a potent anorectic agent when administered into the CSF in mice and at levels that are similar to those reported in plasma of patients with ESRD. [105] [106] [107] Also, the potential toxicities of MMA's oxidation products via the enzyme SSAO—hydrogen peroxide and formaldehyde—may injure vessels, which are a major site of SSAO activity.[108]
3-Carboxy-4-Methyl-5-Prophy-2-Furanpropanoic Acid
The literature on 3-carboxy-4-methyl-5-prophy-2-furanpropanoic acid (CMPF) further illustrates many of the difficulties encountered in the study of uremic solutes. CMPF was identified in the urine by 1950. It was subsequently shown to accumulate in the plasma as renal function is lost and to bind so tightly to albumin that it is scarcely removed by conventional hemodialysis. [74] [109] It has attracted interest because its occupation of albumin-binding sites contributes to the reduced binding of both other endogenous solutes and drugs in uremic patients. [110] [111] But its biochemical source, rate of production, and routes of clearance in both normal subjects and uremic patients remain to be defined. Wide variation in the levels reported in uremic patients further suggests that there are unrecognized differences among assay methods for CMPF. It has been hypothesized that CMPF causes neurotoxicity by interfering with the transport systems that remove toxic organic molecules from the CSF.[112] But investigation has proceeded slowly without stronger evidence of toxicity. Other furancarboxylic acids also accumulate in uremia but in much lower concentrations.[110]
Myoinositol and Other Polyols
Plasma concentrations of a number of polyols increase in uremia. The compound that is found in the highest concentration and has been studied most extensively is myoinositol (see Fig. 47-1 ). [113] [114] Myoinositol is different from most other uremic solutes in that it is normally oxidized by the kidney. Its accumulation in uremia, therefore, reflects impaired degradation and not impaired excretion. The amount of myoinositol excreted in the urine actually increases along with the plasma level as less myoinositol is degraded by failing kidneys.[114] Early studies of myoinositol focused on its potential contribution to uremic polyneuropathy. But evidence that myoinositol causes nerve damage, although stronger than most of the evidence for the toxicity of uremic solutes, is far from conclusive.[115] Other polyols including mannitol, sorbitol, arabitol, and erythritol accumulate in uremia to a lesser degree. [113] [114]They are commonly discussed together with myoinositol but do not have similarly important roles in normal phospholipid metabolism and have not been considered significant contributors to uremic toxicity.
Other Uremic Solutes
The purine metabolite uric acid is the only organic substance whose plasma level is known to be actively regulated by variation of its renal excretion. When renal failure is advanced, the capacity of the kidney to increase the fractional excretion of uric acid is exceeded, and uric acid levels increase along with those of its precursor molecules xanthine and hypoxanthine. Other nucleic acid metabolites excreted by the kidney are produced in much lesser quantities. Many are derived from the modified nucleosides contained in tRNAs.[116] They appear to be cleared largely by filtration and to accumulate in the plasma as the GFR falls. It has been suggested that pseudouridine, which is the most abundant of these substances, contributes to insulin resistance and altered CNS development, but as usual, the demonstration of its toxicity is not conclusive. [116] [117]
Oxalate is also excreted by the kidney and accumulates in renal failure. The plasma concentration of oxalate, which is derived from plant foods as well as from endogenous catabolism of substances including vitamin C, varies widely. [118] [119] Very high levels have been found in patients consuming oxalate-rich diets and taking vitamin C, and deposition of calcium oxalate in skin, heart, and other tissues has been observed in some cases.
A number of studies have identified abnormal polyamine levels in uremia, although there is no clear reason why renal failure should effect the metabolism of these largely intracellular substances. Early studies suggested that levels of putrescine, cadaverine, spermidine, and spermine were elevated in patients with renal failure, and several studies suggested that accumulation of polyamines was responsible for reduced erythropoesis. [2] [120] More recent studies have found that plasma levels of spermidine and spermine are decreased in patients with renal failure, whereas levels of putrescine are only moderately elevated.[121] The focus of these latter studies has been on the hypothesis that accumulation of acrolein produced during the degradation of polyamines leads to the production of modified proteins.
Additional substances excreted by the kidney that accumulate in renal failure include various pteridines and dicarboxylic acids. [116] [122] [123] The list of uremic solutes is lengthening as improved analytic methods identify solutes present in low concentration. The possibility of toxicity is invariably considered when new solutes are identified, but experiments to test the toxicity of uremic solutes are now rarely performed.
Solute Removal by Different Forms of Renal Replacement Therapy
Although investigators have not succeeded in replicating uremic illness by administering uremic solutes to normal humans or animals, reversing illness by removing solutes has become a part of everyday practice. The difficulty is that renal replacement therapies remove solutes indiscriminantly, so that the improvement they effect cannot be attributed to removal of any individual compound. Different forms of renal replacement therapy do, however, clear solutes at different rates based on characteristics including molecular size, protein-binding, and sequestration within cells or other body compartments. The demonstration that different therapies have different effects on some feature of uremic illness might, therefore, reveal the properties of the responsible toxin.
The Original Middle Molecule Hypothesis
The suggestion that the nature of uremic toxins could be deduced by comparing the effect of different renal replacement methods was first advanced by Scribner and colleagues.[124] In the 1960s, hemodialysis was performed with membranes that provided very limited clearance of solutes with molecular weight less than 1000 D. Treatment with these membranes wakened patients from coma, relieved vomiting, and partially reversed other uremic symptoms. This provided evidence, which remains convincing, that some important uremic toxins are small. But Scribner and colleagues[124] were impressed that patients on peritoneal dialysis were healthier than patients on hemodialysis who had the same urea and creatinine concentrations. They further observed that increasing the dialysis duration from 6.5 to 9 hours three times weekly prevented neuropathy. These observations led them to conclude that important toxins had size greater than 300 D, because compared with contemporary hemodialysis membranes, the peritoneal membrane afforded greater relative permeability in this size range and because increasing the dialysis duration was expected to reduce the concentration of large molecules more than the concentration of creatine and urea. Based on their further impression that no additional benefit was obtained using membranes that provided superior clearance for solutes with size greater than 2000 D, they concluded that some important toxins were “middle molecules” with molecular weight greater than 300 D but less than 2000 D.[125]
Large Solutes—the Changing Definition of “Middle Molecules”
Only equivocal evidence was obtained during the 1970s that increasing the clearance of solutes with molecular weight between 350 D and 2000 D improved the health of uremic patients.[124] The proposition that no benefit could be obtained by increasing the clearance of solutes with molecular weight greater than 2000 D was never prospectively tested. The original “middle molecule hypothesis” was thus never proved to be correct. In addition, although the phrase middle molecules remains in use, its meaning has gradually shifted to include larger solutes. The 2003 report of the EUTox group[1] thus defined middle molecules as having a size greater than 500 D and less than 60,000 D, which is nearly the size of albumin. In practice, the adoption of new membrane materials, which was in part a response to the original middle molecule hypothesis, has ended investigation of the relative toxicity of solutes that fall in different parts of the size range less than 1000 D. The question of whether solutes with molecular weight greater than 1000 D exert toxic effects remains under investigation. Henderson and associates[126] showed that such solutes can be cleared more effectively by hemofiltration than by hemodialysis. Whereas maintenance hemofiltration has been practiced on a small scale for many years, its benefit as compared with hemodialysis remains to be established. Increasing large solute clearances to the extent that this can be accomplished by hemodialysis using “high-flux” as compared with “low-flux” membranes was not found to have any benefit in the Hemodialysis (HEMO) study.[127]Practically all of the known examples of solutes with size greater than 1000 D are peptides. The only one so far proved to be toxic, and indeed the one that has been extensively studied, is β2-microglobulin that has a molecular weight of approximately 12,500 D. It should be noted that, even when high-flux membranes are used, clearances of large solutes obtained by hemodialysis are much lower, in comparison to the clearance provided by the normal kidney, than the clearances of urea and creatinine. For β2-microglobulin, the reduction in plasma levels obtained by shifting from low-flux to high-flux membranes is modest, further suggesting that most of its clearance is accomplished by means other than dialysis.[128] Studies that achieve higher clearances of large solutes and include solutes other than β2-microglobulin are required to assess the contribution of large solutes to uremic illness.
Protein-Bound Solutes
Another group of solutes that are poorly removed by standard hemodialysis includes those that bind to albumin. [3] [74] [75] [129] Their dialytic clearance is low not because they are large molecules, but because only the free, unbound solute concentration contributes to the gradient driving solute across the dialysis membrane. When expressed as multiples of normal, levels of these compounds are, therefore, much higher than levels of unbound solutes like urea and creatinine in hemodialysis patients.[75]
Small solutes bind competitively to albumin at a number of sites.[130] One effect of the aggregate accumulation of protein-bound solutes in uremia is to decrease the binding of individual substances.[131] Thus, uremic patients exhibit an increase in the unbound fractions of the amino acid tryptophan and of drugs including phenytoin, furosemide, salicylate, and many others. The decreased drug binding observed in uremic plasma has so far not been fully replicated by addition of known uremic solutes to normal plasma, and our current list of the protein-bound solutes that accumulate in uremia is undoubtedly incomplete.[132] But there is reason to suspect that at least some of the protein-bound solutes that accumulate in uremia are toxic. The normal kidney achieves high clearance rates for many protein-bound solutes by active tubular secretion. Presumably, the combination of protein-binding and tubular secretion represents an evolutionary adaptation that allows for excretion of toxic molecules while keeping their concentrations in the ECF very low.[94]
In vitro evidence has been obtained for the toxicity of some protein-bound solutes, but as usual, this evidence is not conclusive. [112] [133] The aggregate toxicity of protein-bound solutes could theoretically be assessed by comparing the effect of different renal replacement prescriptions, but this has not been attempted in practice. Mathematical models predict that hemofiltration, which removes large solutes more effectively than routine hemodialysis, removes protein-bound solutes less effectively. But clinical studies to test this prediction have not been performed. Recent studies have shown that peritoneal dialysis clears protein-bound solutes at a very low rate and that removal of protein-bound solutes in patients maintained on peritoneal dialysis depends heavily on residual renal function. Studies have not yet been performed in peritoneal dialysis patients without residual function, in whom protein-bound solute levels would be predicted to be very high.
Sequestered Solutes
Some solutes are sequestered, or held in compartments in which their concentration does not equilibrate rapidly with that of the plasma.[135] Application of a high dialytic clearance may rapidly lower the plasma concentration of such solutes while removing only a small portion of the total body content. When this happens, intermittent dialysis treatment will be followed by a rebound in the plasma solute concentration toward predialysis levels.
The effect of sequestration on the removal of urea, which is generally used to assess dialysis adequacy, is modest.[3] It is widely assumed that many organic solutes equilibrate more slowly than urea between compartments such as cell water and the plasma. Studies demonstrating sequestration of creatinine, uric acid, and several guanidines are consistent with this assumption, but the behavior of other solutes has not been examined. [42] [136] [137] Theoretically, the contribution of sequestered solutes to uremic toxicity, like the contribution of large solutes or protein-bound solutes, could be assessed by comparing the efficacy of different dialysis prescriptions. When treatment is intermittent, the removal of sequestered as compared with freely equilibrating solutes can be increased by lengthening the treatment while reducing the plasma clearance. It has been suggested that this effect may be responsible in part for the exceptional results reported with slow, thrice-weekly hemodialysis.[138] But available studies are not sufficiently well controlled to confirm the importance of sequestered solutes.
Effects of Diet and Gastrointestinal Function
It may be possible to identify uremic toxins by comparing the effect of different diets as well as by comparing the effect of different renal replacement therapies. Patients with renal failure tend spontaneously to reduce their intake of protein.[139] In addition, before dialysis became available, physicians found that protein restriction relieved uremic symptoms.[140] These findings suggest that important uremic toxins are derived from protein catabolism. Uremic solutes whose production has been shown to depend on protein intake include urea, methylguanidine, guanidinosuccinic acid, and the indoles and phenols that are produced by the action of gut bacteria on tryptophan, phenylalanine, and tyrosine. [50] [61] [141] [142] [143] The dependence of most other solutes on dietary protein is unknown, and the effect of the intake of individual amino acids on uremic solute production has not been studied. It seems likely that uremic toxins can also be derived from other dietary constituents and that uremic patients may have limited tolerance for certain foods just as they have limited tolerance for certain medications. Dialysis patients have become comatose following ingestion of star fruit, a member of the Oxalidaceae family.[11] But given the variety of chemicals contained in plants, there are remarkably few reports of this kind.[144]
The production of uremic toxins may depend not only on dietary intake but also on gut function. Uremic solutes made by colonic bacteria include methylamines as well as some indoles and phenols.[104] The production of these compounds in uremic patients may be increased by impaired small bowel function, which increases delivery of their precursors to colonic bacteria, or by the penetration of colonic bacteria into the ileum. [99] [145] If colonic bacteria produce uremic toxins, uremic symptoms could theoretically be relieved by reducing colonic transit time or by altering the colonic flora. But only limited studies of such maneuvers have so far been performed. [102] [146]
Solute Excretion by Tubular Transport Systems
The cloning of transporters that move organic solutes into the lumen of the proximal tubule has provided a possible new route to the identification of uremic toxins. To the extent that uremia is caused by accumulation of organic solutes, knocking out these transporters would be expected to reproduce uremic symptoms. To date, knocking out both of the organic cation transporters 1 and 2 has been shown to abolish tubular secretion of organic cations without causing detectable illness.[147] Similarly, mice in which the organic anion transporter 1 has been knocked out exhibit a reduced clearance for para-aminohippurate and other organic anions but otherwise appear normal.[148]Redundancy of the transport mechanisms for important toxins and the residual clearance provided by glomerular filtration may limit the effects of deleting transport molecules.
METABOLIC EFFECTS OF UREMIA
The loss of renal function has numerous metabolic effects. A few of these can be related to the loss of specific renal processes such as the hydroxylation of vitamin D. But most have no clear cause and can at present be attributed only to the retention of uremic solutes. The endocrine aspects of uremic metabolism are described in Chapter 50 , and other metabolic effects of uremia are described later.
Oxidant Stress and the Modification of Protein Structure
Recent studies suggest that loss of kidney function increases oxidant stress.[149] The term oxidant stress is acknowledged to be vague. Moreover, as is the case with uremic solute retention, the changes that are easiest to measure may not be the most important contributors to illness. However, a variety of evidence points to increased oxidant effects in uremia. Increased levels of primary oxidants cannot be documented because they are evanescent species that act locally like superoxide anion, hydrogen peroxide, hydroxyl radical, and hypochlorous acid. The accumulation of various products of oxidant reactions is, therefore, taken as evidence of increased oxidant activity. Whereas the accumulation of these markers of oxidant activity is well documented, there is at present no explanation why the production of oxidants should be increased in uremia, except that increased quantities of hypochlorous acid may be released by phagocytes when uremia is accompanied by systemic inflammation.
Among the most commonly measured markers of oxidant activity are malodialdehyde and the other incompletely characterized substances that react similarly with thiobarbituric acid. But the accumulation of these low-molecular-weight compounds could reflect reduced renal clearance as well as increased production. More convincing evidence of oxidant stress is the accumulation of proteins containing oxidized amino acids. [150] [151] The accumulation of these larger markers of oxidation cannot be attributed to reduced renal clearance. Further potential evidence of oxidative stress in uremia is the loss of extracellular reducing substances. The extracellular compartment is normally provided with several reducing substances, of which the reduced forms of ascorbic acid and plasma albumin are considered to be the most important. Presumably, oxidation of these “sacrificial reductants” limits damage to more valuable molecules when oxidants enter the ECF. In uremia, the portion of ascorbic acid and albumin circulating in the oxidized form is increased. The case of albumin, which undergoes oxidation at its single free cysteine thiol (SH) group, is particularly interesting. Plasma albumin in uremic patients is rapidly restored to the reduced form during hemodialysis.[152] The shift to oxidized albumin in untreated uremia is associated with the accumulation of cystine, which is the oxidized form of the thiol amino acid cysteine, and the shift back to reduced albumin during hemodialysis is associated with a lowering of cystine levels toward normal. One explanation for these phenomena is that increased oxidant production causes increased oxidation of albumin and cysteine in uremia. An alternate explanation is that normal renal function is required to accomplish the steady reduction of cystine and albumin that must take place to offset normal oxidant production. Either way, loss of renal function would be associated with an increase in the ratio of oxidants to reductants in the extracellular compartment.
The major ill effect of increased oxidant activity in uremia is believed to be modification of proteins. Proteins are modified not only by direct oxidation of amino acids but also by combination of amino acid side chains with carbonyl 
compounds. The terminology in this area is confusing. The first carbonyl compounds shown to react with proteins were sugars, and the modified proteins formed after several reaction steps were, therefore, referred to as advanced glycation products (AGEs). Elevated sugar concentrations could account for the increased AGE levels found in diabetic patients, but not for the subsequent findings of similarly increased AGE levels in uremic patients. Recent studies have shown that the high levels of active nonsugar carbonyls are responsible for the increased production of these modified proteins when renal function is reduced.[153] The active carbonyls have not been fully characterized, but they include compounds like glyoxal (see Fig. 47-1 ), which can be produced by oxidation of both sugars and lipids. It has, therefore, been suggested that the protein end products of carbonyl modification in uremia should be referred to not as advanced glycation end products but as advanced glycoxidation and lipoxidation end products. Terminology aside, interest in both directly oxidized and carbonyl-modified proteins has centered on the possibility that alterations in protein structure contribute to uremic illness. Evidence has been gathered both for and against the important hypothesis that modifications of protein structure are responsible for accelerated atherosclerosis in uremic patients. [149] [154] [155] A contribution of modified proteins to dialysis-related amyloidosis and skin pigmentation has also been identified. [154] [156] It should be noted that modified protein structures are not believed to contribute to acutely reversible ill effects of uremia like confusion or nausea but rather to cause gradual changes in tissue structure. The importance of such changes has likely increased as life with uremia has been extended by dialysis.
Resting Energy Expenditure
Resting energy expenditure has been reported as increased, decreased, and normal in people with renal failure. [157] [158] [159] [160] [161] Choosing appropriate control populations as well as other methodologic issues such as the corrections for altered body composition have probably contributed to this uncertainty. However, uremia apart from replacement therapies likely reduces resting energy expenditure. For example, energy expenditure falls with GFR in patients studied across a range of subnormal but not end-stage GFRs. [159] [161] Also, in a study with careful attention to its control group and modern measurements of body composition by bioelectric impedance, a lower caloric use of 1325 kcal/day was noted in people with an average creatinine clearance of 29 mL/min compared with that of 1448 cal/day in the normal controls.[161] The lower energy expenditure also accords with rather consistent observations of lower body temperatures in uremia, although additional factors may be at play in thermoregulation.[7] The situation becomes more complex when patients on renal replacement therapy are considered. Indeed, it is in this setting that some studies have reported higher than normal energy expenditure and that hemodialysis may further enhance metabolism.[160] Effects of inflammatory states in treated ESRD add yet another complexity to assessment of energy requirements.[162]
The lower metabolic rates in untreated uremia are likely to be of multifactorial origin. Lean body mass tends to be diminished with renal disease, and it is a major determinant of energy expenditure.[161] However, diminished food intake may also influence basal metabolic rates and are often reduced.[163] Contributions of retention solutes have been suggested.[164] Finally, the normal kidneys themselves constitute an appreciable energy requirement given their high blood flow, filtration, and attendant transport work. Thus, loss of this basal renal function has been suggested as another component of the fall in energy use with kidney failure. [159] [165]
Carbohydrate Metabolism
Insulin resistance is the most conspicuous derangement in uremic carbohydrate metabolism.[166] The defect is clearly present in ESRD, but in cross-sectional studies, impairment can be detected when GFR falls below 50 mL/min/1.73 m2 with a graded relation to GFR. [167] [168] There are probably several causes of this phenomenon. However, several obvious possibilities do not seem to contribute. Insulin binding to its receptor operates normally in uremia, and the receptor density is unchanged. [169] [170] Also, excess levels of glucagon or fatty acids do not account for the disorder.[166] Several hormones derived from fat, such as leptin, resistin, and adiponectin, accumulate with renal insufficiency. However, their correlations with measures of resistance are poor, and hence, these accumulations seem to be insufficient as explanations. [166] [171]
Because dialysis, transplantation, and low-protein diets each improve insulin responsiveness, some authorities have suggested that a yet-unidentified nitrogenous product mediates the insulin resistance.[166] In keeping with this possibility, an oral sorbent has improved the insulin response in uremic rats.[172] However, the exact factor(s) removed by therapies and presumably diminished in its production by low-protein diets remain unknown. Acidosis is also relieved by dialysis, transplantation, and protein restriction. Because acidosis provokes insulin resistance and its treatment ameliorates the resistance, acid accumulation as well as nitrogenous wastes may contribute.[173] Finally, physical inactivity diminishes insulin action, and as patients become uremic, they tend to become deconditioned with probably a secondary contribution to insulin resistance. Indeed, exercise programs can mitigate the metabolic defect but must be relatively protracted with frequent training. [174] [175] Thus, uremic retention solutes including acid as well as simple inactivity likely constitute the major pathways to uremic insulin resistance.
Insulin resistance seems to have adverse effects. Most importantly, it has been recognized as a risk for cardiovascular disease.[176] The connections between insulin resistance and vascular disease are not entirely clear. Of course, a tendency to hyperglycemia is one toxic effect. Also, some but not all investigators have suggested that renal salt retention stimulated by insulin may remain relatively sensitive with arterial hypertension as a result. [177] [178] Another deleterious effect of insulin resistance outside of vascular disease might be loss of its anabolic action with consequent muscle wasting often seen with uremia. [166] [179]
Even though insulin resistance is the rule in uremia, hypoglycemia can be a significant effect of renal insufficiency.[180] Hypoglycemia is likely to occur despite insulin resistance, for two main reasons. The kidney is a major site of insulin catabolism; thus, insulin-requiring diabetic patients may become hypoglycemic if their insulin doses are not adjusted as GFR declines. In effect, the higher levels of insulin in such patients overcome the resistance. In addition, the kidney is a major site of gluconeogenesis.[180] The liver produces the bulk of glucose in postabsorptive and starvation states, but even in these situations, the kidney produces some glucose. With prolonged fasting, the kidney produces about half of the total glucose. [181] [182] Thus, severe renal disease may predispose to hypoglycemia by prolongation of the duration of insulin action and by reduction in gluconeogenesis, and these effects may be particularly apparent if other hypoglycemic factors such as ethanol ingestion or liver disease are at work.
Amino Acid Metabolism
Protein and amino acid metabolism can be deranged in uremia. Indeed, low serum albumin in ESRD patients is common and highly predictive of risk for death.[183] However, even absent nephrosis, hypoalbuminemia of some degree is common with renal insufficiency. In data from the Modification of Diet in Renal Disease (MDRD) study,[139] 10% to 15% of subjects with GFRs of 50 to 60 mL/min/m2 had serum albumins below 3.8 mg/dL, and this proportion rose to almost 30% for those with GFRs at 10 mL/min/m2. This probably bespeaks generalized malnutrition often complicated by inflammation and/or acidosis but does not afflict all ESRD or pre-ESRD patients. Apart from these complications, isolated protein dysmetabolism is of at most modest effect in chronic kidney disease. Lim and Kopple,[179] in reviewing the topic, concluded that “uremia, per se, does not stimulate net protein catabolism.” Although dialysis may increase the dietary protein requirement somewhat through protein and amino acid losses into the dialysate (and perhaps due to some catabolic effect of the hemodialysis procedure itself), people with renal insufficiency but not on dialysis have no extra protein needs.[179] They can be maintained on low-protein diets and stay in balance so long as acidosis or intercurrent inflammatory events do not occur. Whereas this picture seems accurate, such complications are common and raise the risk of marginal protein diets in the clinical setting.
The normal kidney participates in the metabolism of a number of amino acids. Loss of its function probably accounts for some of the alterations in plasma amino acid levels commonly described in renal insufficiency and ESRD. [2] [184] [185] [186] For example, the kidney converts citrulline to arginine. Loss of this function likely contributes to the increasing citrulline-to-arginine ratio as GFR declines below 50 mL/min/1.73 m2. [185] [186] Similarly, the diminution of renal production of serine from glycine probably underlies the rise in the plasma glycine-to-serine ratio. Rising levels of the sulfur-containing amino acids, cystine, taurine, and homocysteine are especially intriguing in light of their roles in redox balance, which is disturbed in uremia as noted earlier, and the association of homocysteine with cardiovascular disease. [185] [186] [187] However, the mechanism(s) of these changes are unclear. These trends all appear as GFR drops below roughly one half of normal and gradually become more extreme at ESRD approaches. The pathophysiologic import of these changes is largely uncertain.
Metabolic acidosis, of course, attends renal insufficiency and, in its own right, causes protein catabolism. Base supplements can mitigate these catabolic effects of acidosis. [173] [188] [189] Acidosis stimulates the ubiquitin-proteosome pathway of intracellular protein degradation. In addition to these effects of acidosis, it contributes to insulin resistance and thereby attenuates insulin's protein anabolic actions. Finally, activation of caspase-3 seems to be an important step in proteolysis followed by disposal of cleavage fragments through the proteosome.[190]
Lipid Metabolism
Nephrotic syndrome and probably even lower-grade proteinuria are regularly associated with hyperlipidemia.[191] However, lipid abnormalities are of small proportion in renal insufficiency without major proteinuria. Indeed, total cholesterol falls as GFR drops below about 30 mL/min/1.73 m2.[139] With respect to potentially hazardous changes, falls in high-density lipoprotein (HDL) and rises in triglycerides have been described. Low-density lipoprotein (LDL) levels are usually not elevated and may be less than in those in normal controls.[191] The causes for these trends are unclear, although the decline in total cholesterol is taken to reflect, at least in part, progressive malnutrition. Even though the abnormalities are not quantitatively striking, the high rate of cardiovascular disease in the population with renal insufficiency has led to trials attempting to lower levels and reduce this risk. The largest trial in ESRD subjects with type 2 diabetes found no beneficial effect of cholesterol lowering with a statin.[192] Whether the rate of decay in renal function can be influenced by lipid lowering is untested in a large trial. Potential effect in preserving renal function has been suggested by animal studies and small trials in humans.[191]
SIGNS AND SYMPTOMS OF UREMIA
The level of renal function at which uremia can be said to appear is obscure. There is no easily definable point in the fall of GFR when uremia supervenes. Furthermore, declines in several renal functions, not only glomerular filtration, are likely to confer symptoms and signs of uremia. In general, other functions such as ammoniagenesis, erythropoietin, and 1,25-hydroxy vitamin D syntheses, concentrating capacity, and tubular secretion are believed to track roughly with GFR. Nevertheless, defining the level of renal function solely by GFR may be, at least in part, misleading. For example, certain potentially toxic retained solutes appear to be depend more on tubular secretion than GFR for their excretion, and the synthetic processes are probably linked to GFR only by virtue of general loss of functioning renal tissue. However, until particular renal dysfunctions are attached to specific aspects of the uremic syndrome, GFR will remain the principal index of renal function.
Most of the characteristics of uremia both clinical and biochemical have been defined in ESRD or at a level of GFR very near ESRD. Thus, as noted at the beginning of this chapter, in contemporary practice, uremic characteristics may be hard to dissect from complications of the dialysis procedure. Other comorbidities that are in principle separate from the uremia also commonly coexist with it. For example, the cardiovascular disease suffered especially by diabetic and hypertensive ESRD patients may be accelerated in some fashion by renal disease, but their myocardial infarctions, strokes, and peripheral vascular disease would traditionally not be considered pieces of the uremic syndrome. These conditions nevertheless add to the disability of the typical patient and often in ways that are not easily distinguishable from uremia or the “residual syndrome” of ESRD. Similarly, peripheral neuropathy and gastroparesis of diabetes are difficult to disentangle from uremic neuropathy and uremic anorexia, nausea, and vomiting.
Well-Being and Physical Function
Quality of life declines in people with chronic kidney disease. This is not so surprising given the well-known range of symptoms attributable to severe renal insufficiency (see Table 47-1 ). However, in recent years, investigators have quantitated quality of life, and efforts to relate it to level of renal function have begun to appear. Various questionnaires have been employed to assess this complex attribute, and worse scores compared with those in normal controls have been the consistent finding. The point in the course of renal disease at which quality of life begins to decline has not been dissected in great detail, but some data exist. In reviewing this area, the authors of the Kidney Disease Outcomes Quality Initiative (KDOQI) guideline concluded that notable reductions in well-being appeared when GFR was less than 60 mL/min.[193] For example, subjects in the MDRD study with GFRs all less than 55 mL/min/1.73 m2 were queried with several survey instruments and reported fatigue and reduced stamina that correlated with GFR.[194] In another study using the Medical Short Forms–36, people with GFR less than 50/mL/min/1.73 m2 but not yet at ESRD scored lower than the general population in 8 of the 10 scales composing the instrument.[195] Although these latter investigators could detect no gradient related to GFR within the group with depressed GFR, hemoglobin level did correlate with the scores.[195] Furthermore, patients with ESRD being treated with dialysis scored lower than those with renal insufficiency on all scales. By contrast, some studies using different questionnaires have found better quality of life in dialysis patients than in those predialysis. [196] [197] However, transplantation and elevation of hemoglobin with erythropoietin have rather consistently been found to improve quality of life. [198] [199] Thus, patients with renal insufficiency and GFRs below 50 mL/min/1.73 m2 generally have measurably diminished quality of life.
Physical functioning in patients treated with dialysis is decidedly below normal. The exercise capacity of these ESRD patients has been found to be about 50% of predicted, with a range of 40% to 80%.[200] Treatment of anemia improves this situation but does not normalize it. [200] [201] The most detailed studies have found a set of defects that associated with easy fatigue.[202] These include both reduced muscle energetic failure and neural defects. The degree to which these lesions were attributable to the uremic environment itself, deconditioning of the patients and the effects of their comorbidities has not been completely analyzed. Even selected highly functional dialysis patients display notable physical limitations. Blake and O'Meara[203] have reported that among subjects who are middle-aged dialysis patients with good nutrition and no significant comorbidities, a wide range of quantifiable deficiencies exist. For example, balance, walking speed, and sensory function were all clearly below those of matched controls.
Whereas a definite diminution in function is prevalent in ESRD patients, the stage of renal disease at which defects appear has not been thoroughly assessed. One study of nondiabetic men less than 60 years old with GFRs less than 30 mL/min but not yet requiring dialysis found an exercise capacity that was relatively well maintained at 94% of the reference value.[204] Conversely, the same investigators,[205] using different measures, found a clear reduction in strength in subjects older than 60 years with GFRs less than 25 mL/min. Data from the National Health and Nutrition Survey III (NHANES III) show a gradual increase in the fraction of subjects who believed they could walk one quarter mile from about 5% at normal GFR to 15% at a GFR of 15 mL/min/1.73 m2.[193] Thus, it is difficult to ascertain at what point in the course of progressive renal disease measurable declines in strength and exercise capacity appear, in part because different measures including the subjects' own estimates have been employed. However, functional impairment surely occurs before ESRD but may be hard to discern unless GFR is below 60 mL/min/1.73 m2.
Neurologic Function
Sensorimotor neuropathy was an early recognized component of the uremic syndrome.[7] However, it was usually assessed by measuring nerve conduction velocity and studied only at ESRD or very low GFR. Using conduction velocity and other tests, the majority of ESRD patients have neuropathy, albeit often subclinical. [206] [207] Hence, reductions in conduction velocity clearly occur at these late stages, but whether they begin to fall at higher levels of GFR is not certain. As with other uremic disturbances, the cause is unknown. PTH, multiple retention solutes, and more recently, potassium have been associated with peripheral neuropathy but without definitive proof of causality.[206] [207] Cognitive function can be severely disturbed in untreated uremia and can manifest as frank coma or catatonia relieved by dialysis.[206] Modern ESRD patients seem to show more subtle cognitive defects.[208] This seems likely if only because several studies suggest that impairment can be detected when GRF drops below 60 mL/min/1.73 m2 and worsens as GFR falls. [209] [210] As with other functions, the degree to which cognition is influenced by uremia as opposed to other comorbidities, especially cerebrovascular disease, is difficult to ascertain, but clinically recognized vascular disease and other comorbidities were considered in these analyses. Subclinical cerebrovascular disease appears to be common in the population with renal insufficiency, and its role in poor cognition needs further definition. [208] [211]
Appetite, Taste, and Smell
Energy intake including protein intake declines as GFR does.[139] As with most of the abnormalities outlined previously, these phenomena appear to become detectable when GFR falls below about one half normal. Decrements in resting metabolism and physical activity diminish energy requirements and may appropriately dictate lesser intake.[161] How-ever, an independent and clearly pathologic anorexia also supervenes as witnessed not only at end-stage but also by falling serum albumin levels with lesser renal insufficiency.[139] In the NHANES III data, albumin levels begin to decline with estimated GFRs in the range of 50 to 60 mL/min/1.73 m2.[193] A large number of pathways have been proposed as contributing to uremic anorexia. Acidosis, various inflammatory cytokines such as TNF and interleukins, and the adipogenic hormone leptin have been suggested as anorexigenic factors. [212] [213] [214] In addition to those factors inhibiting appetite, erosion of taste and smell has been long recognized and has been found almost ubiquitous in the ESRD population. [215] [216] As with most defects, transplantation reverses the blunted smell.[215] Odor threshold appears to decline gradually with creatinine clearance.[215] Taste acuity has been reported as lower in dialysis patients than in those with renal insufficiency.[217] The factors responsible for these defects are unknown.
Cellular Functions
The most general cellular abnormality reported has been the inhibition of sodium-potassium ATPase (Na-K-ATPase). Decreased Na-K-ATPase activity in red cells of uremic patients was reported in 1964.[218] In general, subsequent reports have confirmed the observation, noted the same effect in other cell types, and emphasized that the inhibition was attributable to some factor in uremic serum.[219] The evidence for a circulating inhibitor includes the findings that dialysis reduces the inhibitory activity, and uremic plasma can acutely suppress the pump activity.[219] However, the factor or factors have remained elusive. A number of candidates have been considered. Most attention has focused on digitalis-like substances. Recently, several such compounds have been found in excess in humans with ESRD. These include marinobufagenin and telocinobufagin, which have structures related to digitalis. In one report, the plasma levels of each of these substances was four- to fivefold higher in ESRD patients compared with normal controls.[220] This particular study had the advantage of detailed mass spectrometry and nuclear magnetic resonance identification of the compounds with their concentrations determined by high-performance liquid chromatography. Many other investigations in the field have relied on antibody-based assays whose specificity may be less dependable. However, even should the elevations in these factors be confirmed, several issues remain to be resolved.
The compounds, including other digitalis-like factors, have generally been sought as endogenous products. The two compounds noted previously may be made by other animals, and some others, but apparently not these two, are synthesized by plants (as, of course, is digitalis). The question of overproduction, the dominant theme of the investigations in the field as opposed to accumulation of ingested material owing to loss of renal function, has not been settled or much addressed. One study of uremic rats reported an increased plasma level and urinary excretion of marinobufagenin.[221] Because both the excretion rate and the plasma level were about double the control levels, the results suggest that overproduction may be solely responsible for the increased plasma level and that the lower renal function in these subtotally nephrectomized rats played very little role. Similar measurements of the excretion or production for other digitalis-like compounds in humans or even in animals are not available.
If overproduction (and the data are not extensive for it) is the major cause of the higher plasma concentration of the digitalis compounds, the organ producing them and the stimuli to their secretion become important questions. The hypothalamus and the adrenal cortex have been the most studied as sources. [222] [223] Both sites have been incriminated as sources of digitalis-like substances. Most studies have focused on various forms of experimental hypertension, and the relative roles of these two loci in uremia have not been addressed. Adrenocorticotropic hormone (ACTH) seems may be a stimulus presumably to the adrenal forms. In any case, mice lacking the cardiac glycoside binding site in their Na-K-ATPase are also resistant to ACTH-induced hypertension.[224] Expansion of the ECF volume has also been proposed as a stimulus.[225] How and where this signal is transduced are obscure. This view would hold that the substance has the effects of increasing cardiac output by cardiotonic digitalis-like actions and causing vasoconstriction through an effect on calcium entry in smooth muscle. These actions are proposed as promoters of hypertension, at least when sodium excretion is limited by renal disease.
Several considerations militate against digitalis-like substances as mediators of uremic toxicity. Some of the classical features of digitalis toxicity such as atrioventricular nodal conduction delays, ventricular extrasystole, and visual disturbances are not prominent even in older descriptions of untreated uremia. Other toxicities of digitalis such as anorexia are, of course, common with uremia.
The relation of Na-K-ATPase inhibition to GFR has not been much explored. Most studies have employed sera from patients or animals with complete renal failure although some, such as a study of marinobufagenin in rats have used models of renal insufficiency.[221] Also, a report examining the depression in muscle membrane potential in humans with ESRD showed not only that the electrophysiologic abnormality was improved by dialysis but also that it was detectable only at a GFR below about 10 mL/min/1.73 m2.[226] This depression in muscle membrane voltage would be consistent with Na-KATPase inhibition, and if so, it seems a late event in the course of renal disease.
Why Is Glomerular Filtration Rate So Large?
The disturbances discussed previously are generally undetectable unless GFR is less than one half normal. Thus, one could argue that one half of renal function is superfluous. Because normal renal blood flow accounts for about one fifth of cardiac output, it would seem that a substantial fraction of cardiac output (and energy expenditure) serves no apparent homeostatic purpose. Homer Smith[227] recognized that GFR was large in proportion to identifiable, important solute clearances and proposed that it was an evolutionary residual of the need to excrete water acquired as early vertebrates moved into fresh water from the sea. If so, the seeming superfluity of GFR would appear an expensive vestige in land-dwelling mammals. Supporting structures such as bone have evolved with some safety factor, meaning that they can withstand some multiple of their usual load. Attractive as such an explanation may be for such a safety factor as the explanation for a greater than essential GFR, it begs the question of what that additional load might be. Although no clear conclusion can at present be drawn from these considerations, several suggestions can be offered for the apparent excess of normal GFR.
Fitness in an evolutionary sense may require the concentrations in body water of some excreted solutes to be maintained below the levels at which we detect disease. That is, our clinical criteria for uremic illness may be too coarse to detect the consequences of mild impairment of renal function. One might speculate that disturbances in an important but sensitive parameter, perhaps fertility, growth in children, or peak physical performance, would occur with less than doubling of some retained toxin. However, the sensitive function and the solute(s) that would depress it are unknown. In the same vein, perhaps in the past, various toxins have appeared frequently enough in ingested food and/or were harmful enough that a rather high, constant clearance rate has been worth the metabolic cost. Again, the toxin is unknown. The apparent abundance in GFR has also been attributed to sporadic loads of dietary protein or phosphate. The known wastes of protein intake, urea and acid for the most part, do not seem to require the rates of clearance that usual renal function provides. Theoretically, the large tubular flow rate provided by the GFR could supply a sink into which organic solutes are secreted more favorably than at lower tubular flows. This hypothesis accounts for evolutionary development of a large GFR, but leaves unanswered the question of which solutes must be handled by secretion and thereby maintained at a low level in the ECF.
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