Nutrition, Diet, and the Kidney1

Nutrition, Diet, and the Kidney1

Joel D. Kopple


The kidney has three primary functions: excretory, endocrine, and metabolic. All three functions may be impaired in renal disease and may affect the patient’s nutritional status and management. When injury, necrosis, and scarring of the renal parenchyma cause a loss of renal function, the quantity of the substances that are filtered by the kidney falls. However, many aspects of renal function undergo adaptive changes that preserve homeostasis and minimize the derangements in plasma and tissue concentrations of substances that normally are excreted by the kidney. Prominent among these adaptions are nephron hypertrophy and an increase in blood flow and glomerular filtration rate (GFR) in those nephrons that are still functional. Chronic kidney disease (CKD) has been classified into five stages, as shown in Table 97.1 (1).

Water and many organic compounds and minerals accumulate in renal failure (2). Low-protein diets (LPDs), various minerals, and other compounds reduce accumulation of many of these substances. Eventually, renal failure may become so severe that the aforementioned adaptive mechanisms are no longer adequate to maintain homeostasis,
even with special dietary therapy that restricts the intake of fluid, electrolytes, and protein. The accumulation of these compounds, the endocrine and metabolic disturbances, and the clinical signs and symptoms that result from renal failure are referred to as uremia. If this condition is not treated by maintenance hemodialysis (MHD), chronic peritoneal dialysis (CPD), or renal transplantation, clinical deterioration and death will eventually supervene.




GFR (mL/ min/1.73 m2)



Kidney damage with normal or increased GFR



Kidney damage with mildly decreased GFR


Stages 1-5T if kidney transplant recipient


Moderately decreased GFR



Severely decreased GFR



Kidney failure

<15 (or receiving dialysis therapy)

5D if receiving chronic hemodialysis or chronic peritoneal dialysis

aChronic kidney disease is defined as kidney damage or a glomerular filtration rate (GFR) <60 mL/minute/1.72 m2 for at least 3 months. Kidney damage is defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies.

Reproduced with permission from editors of the American Journal of Kidney Diseases from the National Kidney Foundation KDOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003;42(Suppl 3):S1-201.

Excretion and regulation of body water, minerals, and organic compounds are clearly the most important functions of the kidney. Without renal excretory function, patients rarely live longer than 4 to 5 weeks and often less than 10 days, particularly if they are hypercatabolic. In contrast, anephric patients can be kept alive for years with intermittent MHD or CPD, even though many of the endocrine and metabolic disorders that occur with a failing kidney are not completely corrected.

The kidney elaborates certain hormones that have diverse metabolic effects, including 1,25-dihydroxycholecalciferol, erythropoietin, renin, and kallikreins; these have been reviewed elsewhere (3, 4, 5, 6). Vitamin D3 (cholecalciferol) is hydroxylated in the liver to form 25-hydroxycholecalciferol. This compound is then converted in the kidney to 1,25-dihydroxycholecalciferol (1,25-dihydroxyvitamin D), the most potent natural form of vitamin D (see the chapter on vitamin D). In renal failure, impaired synthesis of 1,25-dihydroxyvitamin D contributes to a vitamin D-deficient state associated with impaired intestinal calcium absorption, hyperparathyroidism, resistance to the actions of parathyroid hormone (PTH) on bone, and the development of renal osteodystrophy. Epidemiologic data suggest that 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D may have other beneficial effects including reducing risk of cancer and cardiovascular disease and mortality (7, 8, 9). These intriguing possibilities await confirmation by controlled prospective clinical trials (10, 11).

Erythropoietin stimulates erythropoiesis in bone marrow (6, 12), and the anemia of chronic renal failure (CRF) is primarily caused by impaired erythropoiesis resulting from reduced erythropoietin production in the diseased kidneys. Compounds that accumulate in renal failure may also suppress erythropoiesis, and mild hemolysis often contributes to the anemia. Recombinant DNA-synthesized human erythropoietin is commonly used to increase the blood hemoglobin levels of patients with advanced CKD and those undergoing maintenance dialysis (MD) (13).

Renin stimulates the conversion of angiotensinogen to angiotensin I, which, in turn, is converted to angiotensin II by angiotensin-converting enzyme (ACE). Angiotensin II is a potent vasoconstrictive agent that raises blood pressure and also may stimulate collagen formation and cell proliferation in the kidney and probably other tissues. Renal renin secretion is stimulated by renal ischemia (e.g., in renal artery stenosis) and sometimes other renal diseases; increased plasma renin levels can cause hypertension. Renal disease, and particularly renal failure, also may engender hypertension by other mechanisms, including the retention of sodium chloride and water.


Kidney function both regulates and is influenced by the body’s pools and concentrations of water, minerals, and many other nutrients and their metabolites.

Effects of Malnutrition on the Kidney

Malnutrition can have important but usually reversible effects on renal function (14). In humans, malnutrition decreases the GFR as well as the capacity to concentrate and acidify urine (14, 15, 16, 17). If nutritional intake improves, these functions may normalize. GFR falls reversibly in obese subjects treated with weight reduction diets or bariatric surgery (18).

The low protein intake leads reversibly to reduced lower renal blood flow and GFR (14, 15). LPDs in rats can cause almost a 35% reduction in GFR, increased resistance in the arterioles leading into (afferent) and out of (efferent) the glomerulus, a 25% reduction in the glomerular capillary plasma flow, and almost a 50% decrease in the glomerular capillary ultrafiltration coefficient (19). A reduction in insulinlike growth factor-I (IGF-I) levels may contribute to these changes (20, 21). Reduction in extracellular body water and circulating blood volume may also decrease renal blood flow and GFR. Increased sodium chloride and water intake reverses this condition.

Malnourished individuals often have lower specific gravity in random urine specimens and therefore increased daily urine volumes. Impaired concentrating ability probably contributes to the nocturia that may occur in malnutrition. The inability of the malnourished patient to concentrate urine normally appears to result from the low protein intake and consequent low rate of urea synthesis (16). Urea is critical for normal urinary concentration. Some of the urea filtered by the glomerulus is reabsorbed in the renal tubule. The urea accumulates in the interstitium of the renal medulla, where, when the collecting duct aquaporin receptors are expressed, urea and other chemicals attract water from the lumen of the distal tubule and collecting duct by osmotic pressure. The loss of water from the lumen of the distal tubule and collecting duct by osmotic pressure increases the concentration of urine. When less urea accumulates in the renal medulla, the ability to attract water from the collecting duct is reduced, and hence the urinary concentrating ability is diminished. The capacity to dilute urine is normal in malnutrition.

Malnourished subjects are more likely to develop acidosis after an acid load (17). Urinary phosphate and ammonia are primary carriers of acid (protons) in the urine. Hydrogen ion secretion into the lumen of the distal nephron lowers the pH of tubular fluid and converts HPO4˜ to H2PO4˜ and stimulates ammonia production and the conversion of ammonia to NH4+. In individuals who have a low phosphorus intake, the phosphate filtered in the kidney is largely reabsorbed; this response conserves body phosphate pools; less phosphorus is excreted in the urine, however, and this reduces the capacity of the kidney to excrete acid. Infusion of phosphate increases urinary excretion of titratable acid in malnourished patients (17). Renal production and excretion of ammonium are also reduced in malnutrition, both under basal conditions and after an acid load (17).

During prolonged starvation, the kidney may account for up to 45% of endogenous glucose production, although part of the rise in the renal contribution to total glucose synthesis is the result of a fall in total body glucose production (22). In extended starvation, net renal extraction of lactate, pyruvate, amino acids, and glycerol also occurs (21). The carbon skeleton in these compounds is virtually completely converted into glucose. During prolonged starvation, free fatty acids and β-hydroxybutyrate are also extracted by the kidney, and acetoacetate is released (22).

Acute starvation and other conditions associated with increased catabolism of nucleic acids, purines, and amino acids, such as may occur with chemotherapy of leukemia and certain other tumors, can cause a marked increase in uric acid production. Hyperuricemia can lead to deposition of uric acid sludge in the kidney and lower urinary tract and may cause acute kidney injury (AKI). Treatment consists of allopurinol, which inhibits the synthesis of uric acid, maintenance of good hydration and a large urine flow, and alkalinization of the urine, because the solubility of uric acid increases markedly in alkaline solutions (23).

Effects of Protein and Amino Acid Intake on Renal Function

Protein intake appears to engender both an immediate and a more long-term increase in renal blood flow and GFR in humans. A transient increase in renal blood flow and GFR of about 20% to 28% occurs about 2 hours after ingestion of a protein or amino acid load and generally lasts about 1 hour (24, 25). Renal blood flow and GFR increase transiently and more quickly following an intravenous infusion of a mixture of essential and nonessential amino acids (26) or a 30-minute infusion of arginine hydrochloride (27). Long-term intake of high-protein diets or LPDs is generally associated, respectively, with chronically increased or reduced renal blood flow and GFR.


Mechanisms of Progression

It has been known for many decades that individuals with CKD who have sustained a substantial loss of GFR often continue to lose renal function inexorably until they develop terminal renal failure (28, 29, 30, 31). Although the rate of progression of renal failure varies greatly among patients, in many individuals the decline in kidney function is linear (28, 29, 30). The percentage of patients with renal insufficiency who will progress to renal failure is not known, but it seems likely that most patients who sustain a loss of GFR of 60% or greater will show continued progression of renal failure. Renal failure may progress because of continued activity of the underlying renal disease or because of the superimposition of other diseases that may contribute to renal injury such as hypertension, adverse effects of nephrotoxic medicines (e.g., antibiotics or radiocontrast material), obstruction, kidney infection, hypercalcemia, or hyperuricemia. However, it is not rare for progression to continue even after the initial cause of the renal disease seems to have disappeared and when superimposed illnesses are not present (32, 33, 34, 35). For example, progression of renal failure may continue in patients who have relief of urinary tract obstruction, control of hypertension, discontinuance of nephrotoxic medications, or partial recovery from acute renal failure.

Studies of animal and in vitro models of CKD or renal failure have led to the following observations. There is a rather common set of physiologic and biochemical responses to chronic loss of renal function, that is, to a large degree, independent of the underlying type of kidney disease. When the loss of functioning nephrons becomes sufficient to cause renal insufficiency, the remaining individual functioning nephrons generally undergo an increase in the glomerular plasma flow and GFR and an enlargement in size of both the glomeruli and the tubules (i.e., nephron hypertrophy) (36, 37). The capillary blood pressure and the blood pressure gradient across the capillary wall in the remaining functional glomeruli increase (37, 38). In addition, the chemical and electrical, as well
as pore size, barriers to the movement of plasma proteins across the glomerulus and into the renal tubule lumen are impaired. This can lead to both proteinuria (leakage of protein into the urine) and deposition of proteins in renal tissue. This, in turn, can stimulate migration of leukocytes and monocytes, platelet aggregation, collagen deposition, cellular proliferation, and other inflammatory and scarifying changes (39, 40). These processes may contribute to progressive renal damage. Many of the foregoing changes, some of which could be considered adaptive physiologic responses, are believed to promote further renal injury. These factors, as well as continuing activity of the underlying renal disease, can lead to progressive renal failure.

Current thinking regarding potential causes of progressive renal failure is summarized in Table 97.2. Most of these processes have been investigated only in animal models, and it is inferred that they may play a role in human renal disease. It is pertinent that many of these mechanisms appear to be susceptible to amelioration or reversal by nutritional therapy (see Table 97.2). For example, protein-restricted diets have been shown to reduce renal blood flow, GFR, and proteinuria in humans with renal disease (27). Albuminuria itself is a risk factor for more rapid progression of CKD, and the magnitude of albuminuria, in general, is correlated with the rate of progression of a given type of CKD.


Continued activity of the underlying renal disease

Systemic hypertensionb

High-protein dietb

High-phosphorus dietb

High-total-fat or high-cholesterol dietb

High-calcium-phosphorus product in serab

Vitamin D overdose (causing hypercalcemia)b

High serum oxalate levels (can be enhanced by high ascorbic acid intake)b


Angiotensin IIb




Inflammatory response in kidney with release of cytokines and monokines

Platelet aggregation in kidney

Increased mesangial matrix production

Deposition of other proteins in glomerulus

Lipoprotein and lipid deposition in glomerulus

Release of growth factors in kidney

Glomerular and tubular hypertrophy

Intraglomerular capillary pressure and capillary blood flow

Intraglomerular transcapillary hydraulic pressure

Increased generation of reactive oxygen metabolites in remaining functional nephrons

Calcium phosphate or calcium oxalate deposition in the kidney

Nephrotoxic medicines (e.g., radiocontrast material, aminoglycoside antibiotics)

Enhanced renal tubular generation of ammonia leading to complement activation

Lead, cadmium toxicity

aFor many of these factors, evidence that they may cause progressive renal failure is derived from animal models or in vitro systems.

b These causes of progressive renal failure may act through one or more of the mechanisms listed in the lower half of this table.

Experimental Evidence for Effects of Nutritional Intake and Nutritional Status on Progression of Chronic Kidney Failure

Proteins and Amino Acids

In experimental animals with renal disease, a high-protein diet stimulates an increase in GFR, glomerular capillary blood flow, blood pressure gradients across the glomerular capillary wall, and enlargement of individual nephrons, whereas an LPD blunts or prevents this response (37). Moreover, normal rats with renal injury who are fed a high-protein diet develop renal failure, and when such animals are fed an LPD, the progression of renal failure is retarded or arrested (41, 42, 43). It has been hypothesized that high protein intake, by increasing both glomerular capillary blood flow and transcapillary glomerular hydraulic pressure, causes progressive renal injury to the basement membrane (filtering wall) of the glomerulus (38, 44, 45).

High-protein diets may also promote renal insufficiency by other mechanisms. These include the following: induction of nephron hypertrophy with activation of growth factors that stimulate cell hypertrophy, proliferation, and scarring in the glomerulus; enhanced oxidation rates in the nephron with increased generation of reactive oxygen species (46); an acid load that stimulates renal ammonium production with activation of complement and elaboration of endothelin (47); generation of angiotensin II, aldosterone, and other hormones that may promote proteinuria or scarring (48, 49); and elaboration of proinflammatory cytokines. An LPD retards or stops progressive renal damage by preventing or reducing these phenomena.

Transforming growth factor-β (TGF-β) plays a central role in scarring of the diseased kidney (50). TGF-β acts on many other mediators that promote renal fibrosis and protein matrix accumulation (51). The degree to which these processes can be modified or slowed by modifications of nutrient intake is not clear. Most of these mechanisms of progression of kidney disease have been studied only in animals, and it is inferred that they are operative in humans. Diets providing soy protein, a vegetable protein, as compared with casein, an animal protein, may more effectively retard the progression of kidney failure in rats with remnant kidneys (52) and possibly in humans with CKD (see later).

Diabetic rats with moderate hyperglycemia develop renal hypertrophy and increased hemodynamics (53), and similar abnormalities occur in the intact kidney of humans with diabetes mellitus. Early during the course of diabetes mellitus, patients develop increased renal blood flow, increased GFR, and large kidneys (54). Ultimately, in a large proportion of these individuals, glomerulosclerosis
occurs, and renal failure supervenes (55, 56). In the early stages of diabetes, strict glucose control may reverse these phenomena.

Metabolites of tryptophan, and particularly indoxyl sulfate, may cause renal fibrosis and more rapid progression of kidney disease. A medication containing activated charcoal that binds these metabolites in the gastrointestinal tract has been shown to reduce fibrosis in kidneys of rats with CKD and to retard the rate of progression of CKD in both rats and humans (57, 58, 59). A large clinical trial to examine the effects of this medication on progression of CKD is currently being conducted in the United States.

Phosphorus and Calcium

As previously indicated, a low phosphorus intake independent of protein intake appears to retard progression of renal failure (60, 61, 62). One theory on the mechanism of action of the low phosphorus intake is that it decreases the deposition of calcium phosphate in kidney tissue and thus may cause further renal damage (61, 62, 63, 64). Indeed, in renal tissue obtained by biopsy or autopsy, there is a direct correlation between the calcium content and the serum creatinine concentration (63). In general, the calcium concentration of renal tissue is increased more in diseased kidneys with more severe renal histopathologic changes. Medications that bind phosphorus in the intestinal tract enhance the effectiveness of dietary phosphorus restriction in reducing the progression of renal failure in animals (60, 62). These drugs are of particular value as an adjunct to dietary phosphorus restriction, because it is difficult to lower dietary phosphorus intake to necessary levels without making diets highly restrictive, unpalatable, and difficult for adherence.

Obesity and Excess Energy Intake

Obesity is a common contributing factor to the development of CKD. Obese individuals frequently have increased renal plasma flow, GFR, and filtration fraction (65). Albuminuria, glomerulomegaly, and glomerulosclerosis are more likely to be present. Obesity increases the risk of CKD by predisposing to diabetic nephropathy, hypertensive nephrosclerosis, and focal and segmental glomerular sclerosis without diabetes mellitus (65). People with obesity also are at increased risk for calcium oxalate and urate stones and for renal cell carcinoma. In people with established CKD, obesity is more likely to be associated with a greater magnitude of albuminuria and a more rate of rapid progression of kidney failure.

Lipids and Lipoproteins

Many animal studies suggest a pathogenic role for dietary fat intake and hyperlipoproteinemia. Rats, rabbits, and guinea pigs fed a high-cholesterol diet develop hypercholesterolemia and progressive glomerulosclerosis and renal failure (66, 67, 68). The lipid composition of renal cortical tissue is altered, and both mesangial cellularity and matrix formation increase (67). Glomerular capillary pressure rises, even though systemic blood pressure is not extremely elevated. The cholesterol-induced renal injury is much greater when cholesterol-supplemented rats have underlying renal diseases. Mesangial cells and monocytes have receptors for certain lipoproteins (69). Monocytes may ingest low-density lipoprotein (LDL) cholesterol and other lipoproteins, and this may initiate a series of biochemical and physiologic processes that promote tissue injury. Drugs that lower serum lipoprotein levels may ameliorate glomerular injury in rats (70). Some small clinical trials in humans suggest that lowering serum lipids with hydroxyglutarate reductase inhibitors (statins) may slow the progression of CKD (71).

In addition to certain growth factors (see earlier), many other compounds may affect renal physiology and the progression of renal failure (2, 6). These include various eicosanoids, angiotensin, and probably aldosterone. The essential fatty acid linoleic acid can be metabolized in the kidney to several families of eicosanoids, including prostaglandins. Prostaglandins have far-reaching effects on the blood flow and blood pressure inside the glomerulus, the propensity for platelets to clot in the glomerulus, and the inflammatory process. Eicosanoids may have antagonistic effects; some increase glomerular blood flow and pressure and may impair platelet clotting, whereas others do the opposite and may also stimulate an inflammatory response. In renal insufficiency, elaboration of certain eicosanoids and other cytokines is increased in the kidney (72, 73), and they appear to play an important role in the complex adaptive processes undergone by the nephron as kidney function deteriorates (74, 75). In various rat models of CKD, feeding or infusions of linoleic acid, vasodilatory prostaglandins, or injections of thromboxane or leukotriene B4 may retard progression of renal failure (76, 77, 78, 79, 80). In rats with Heymann nephritis, dietary protein itself reduces eicosanoid synthesis (81). Hence, the beneficial effects of dietary protein restriction may possibly be partly the result of its effects on eicosanoid production.


Although the foregoing studies in animals indicate an important role for dietary restriction of protein and phosphorus and reduction or increase of certain dietary fats to control progressive renal failure, there is evidence that certain medications may substitute for or possibly add to the benefits of nutrient restriction. Angiotensin II causes vasoconstriction, alters glomerular permeability to serum proteins, and may stimulate mesangial cell proliferation and aldosterone secretion (5). ACE inhibitors (ACEIs) (medications that decrease blood pressure by inhibiting the enzyme that catalyzes the conversion of angiotensin I to angiotensin II) and angiotensin receptor blockers (ARBs) also lower glomerular capillary blood flow and blood pressure gradients across the glomerular capillary wall in rats with renal insufficiency (5, 82). These agents decrease high blood pressure and retard progressive renal
failure in animals and humans, particularly, but not only, in diabetic patients (83, 84, 85, 86, 87). ACEIs and ARBs reduce urinary protein excretion in patients with kidney disease and reduce or abolish microalbuminuria in diabetic and nondiabetic patients (88, 89). Aldosterone increases activity of enzymes in the kidney as well as other organs. These changes engender activation of some cytokines that promote renal fibrosis and collagen matrix formation (90).

Medications that block binding of aldosterone to aldosterone receptors reduce proteinuria in rats and people with CKD and slow progression of CKD in rats (91, 92). The effects of these blockers on progression of CKD in humans are not well established; patients receiving aldosterone receptor blockers must be monitored for hyperkalemia induced by these blockers (91, 92). Antihypertensive medicines also slow progression of CKD by reducing blood pressure.

Human Studies on the Effect of Dietary Therapy on Progression of Chronic Renal Failure

To what extent are the animal data applicable to patients? From the mid-1970s to the present, many, but not all, dietary studies in humans with renal insufficiency have indicated that a low intake of dietary protein and phosphorus will retard the rate of progression of renal failure (93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104). Some evidence indicates that a low protein and phosphorus intake may each act separately to slow progressive renal failure (61). The earlier studies of this question in humans suffered from one or more major defects in experimental design. Later studies, in general, were better designed. Diet studies generally evaluated low-protein, low-phosphorus diets that provide about 0.40 to 0.60 g protein/kg body weight/day or a very LPD containing about 0.28 g/kg/day (e.g., ˜16 to 25 g protein/day). This latter diet was supplemented with 10 to 20 g/day of the nine essential amino acids or of mixtures of several essential amino acids and ketoacid or hydroxyacid analogs of the other essential amino acids (93, 95, 96, 97, 98, 100, 103). These diets were compared with either a more liberal diet containing approximately 1.0 g or more of protein/kg/day and more phosphorus or to an ad libitum diet.

The ketoacid or hydroxyacid analog is structurally identical to its corresponding essential amino acid, except that the amino (NH2) group attached to the second (α) carbon of the amino acid is replaced with a keto group or hydroxy group, respectively. The ketoacid and hydroxyacid analogs can be transaminated in the body to the respective amino acids, although a proportion of the analogs are degraded rather than transaminated. Because the ketoacids and hydroxyacids lack the nitrogen containing amino group on the α carbon, these compounds provide the patient with a lesser nitrogen load. Because they are degraded in the body, they should engender fewer waste products that normally accumulate in renal failure. Ketoacid analogs of the branched-chain amino acids, especially of leucine, may be somewhat more likely to promote protein anabolism, possibly by decreasing protein degradation (105, 106).

The largest and most intensive examination of whether low-protein, low-phosphorus diets retard the rate of progression of renal disease was the National Institutes of Health-funded Modification of Diet in Renal Disease (MDRD) Study (103, 104). This project investigated, in an intention-to-treat analysis, the effects of 3 levels of dietary protein and phosphorus intakes and 2 blood pressure management goals on the progression of CKD. A total of 840 adults with various types of renal disease, but excluding diabetes mellitus, were divided into 2 study groups according to their GFR.

In Study A, 585 patients with a GFR, measured by iodine-148 iothalamate clearances, of 25 to 55 mL/1.73m2/minute were examined. Patients were randomly assigned to either a usual-protein, usual-phosphorus diet (1.3 g/kg standard body weight/day of protein and 16 to 20 mg/kg/day of phosphorus) or to a low-protein, low-phosphorus diet (0.58 g/kg/day of protein and 5 to 10 mg/kg/day of phosphorus) and also to either a moderate or strict blood pressure goal: mean arterial blood pressure 107 mm Hg (113 mm Hg for those >61 years of age) or 92 mm Hg (98 mm Hg for those >61 years of age). Study B included 255 patients with a baseline GFR of 13 to 24 mL/1.73 m2/minute. Patients were randomly assigned to the lowprotein, low-phosphorus diet or to the very-low-protein, very-low-phosphorus diet (0.28 g/kg/day of protein and 4 to 9 mg/kg/day of phosphorus) with a ketoacid-amino acid supplement (0.28 g/kg/day). They were also randomly assigned to either the moderate or strict blood pressure control groups, as in Study A. The adherence to the dietary protein prescription in the different diet groups was good (103).

Among participants in Study A, those prescribed the LPD had significantly faster declines in GFR during the first 4 months than those assigned to the usual-protein diet. Thereafter, the rate of decline of the GFR in the lowprotein, low-phosphorus group was significantly slower than in the group fed the usual-protein, usual-phosphorus diet. Over the course of the entire treatment period, there was no difference in the overall rate of progression of renal failure in the two diet groups. However, it is likely that the initial greater fall in GFR in the patients prescribed the LPD may reflect a hemodynamic response to the reduction in protein intake rather than a greater rate of progression of the parenchymal renal disease. This response could in fact be beneficial, reflecting a reduction of intrarenal hyperfiltration and intrarenal hypertension. If this explanation is correct (and it is not proven that it is correct), the subsequently slower rate of progression of disease after the first 4 months of dietary treatment is consistent with a beneficial effect of this intervention on the renal disease. In Study B, the very LPD group had a marginally slower decline of GFR than the LPD group; the average rate of decline did not differ significantly between the two groups (p = .066).

In the MDRD Study, the very-low-protein ketoacidamino acid supplemented-diet was not compared with the usual protein intake. Moreover, it is possible that the lack of significant effect of the LPD on the progression of renal failure could reflect the rather short mean duration of treatment in the MDRD study—2.2 years. Indeed, if the trend toward slower progression of renal failure in the LPD groups that was present at the termination of the MDRD study had persisted during a longer follow-up period, a statistically significantly slower progression would have been observed with the 0.60 g/kg protein diet in Study A and the very-low-protein, ketoacid-amino acid-supplemented diet in Study B. Several other characteristics of the patient population and study design of the MDRD may have led to the lack of a statistically significant difference in progression of renal failure between the diet groups (107).

It is also reported that vegetarian LPDs providing soy protein may retard progression of CRF more effectively than diets of similar protein content that contain animal protein (52, 108, 109). The mechanisms of such an effect is not known, but it may be related to the total content and different composition of fats in the vegetarian diet. The vegetarian diet is reported to improve the serum lipid profile in patients with CKD and the nephrotic syndrome (109, 110).

Several published metaanalyses have evaluated clinical trials of the effects of LPDs on the rate of progression of kidney failure. In general, the LPDs were also low in phosphorus. These metaanalyses each evaluated a somewhat different series of clinical trials, only some of which included the MDRD study (111, 112, 113, 114). Three of the metaanalyses used, as the key outcome, the onset of end stage renal disease (ESRD) as determined by the patient with CRF who is starting treatment with MHD or CPD or receiving a kidney transplant (111, 112, 114). These metaanalyses reported statistically significant reductions in the relative risk of a patient with CRF assigned to the LPDs reaching this end point to 0.54, about 0.67, and 0.61, respectively. One metaanalysis used the rate of decrease in GFR as the key outcome (113). This last study described a slowing in the progression of renal failure of only 6% which, although statistically significant, was of questionable clinical significance.

The discrepancy between these two sets of findings may be explained in part by the fact that ingestion of LPDs leads to a reduction in the generation of metabolic products of protein and amino acids, and that some of these metabolic products are toxic. Indeed, patients ingesting LPDs are reported to be started on MHD or CPD at lower GFRs than are individuals with higher protein intakes. The fact that LPDs may ameliorate uremic symptoms and delay the need to inaugurate dialysis treatment or renal transplantation can be considered to be an advantage in itself to these LPDs, even if the degree of delay in the rate of progression of CKD is not very large. In this regard, in another study, elderly patients with GFRs of 5 to 7 mL/minute/1.73 m2 were randomly assigned to treatment with MD or with a very-low-protein ketoacid-amino acid diet. The latter patients were treated with the ketoacid diet for 1.0 to 58.1 months (median, 10.7) (115). The patients who were assigned to the ketoacid diet appeared to fare as well clinically and nutritionally as did those who were assigned initially to MD.

The foregoing metaanalyses also examined clinical trials that used an intention-to-treat type of analysis, whereby the data from individuals assigned to a given dietary intake were included in the results, whether or not they adhered to the dietary prescription or even were available for follow-up testing. Thus, these studies do not rule out the possibility that people who adhere closely to these LPDs may not have a significant delay in the rate of progression of their CKD.

Another metaanalysis analyzed the results of five prospective clinical trials of the effects of LPDs on progression of renal failure in patients with insulin-dependent diabetes mellitus (112). This analysis indicated that LPDs also retard progression in these individuals. However, the results were much less definitive because smaller numbers of patients were analyzed; two of the trials had no randomized, concurrent control group, and the key end points were less definitive.

In a secondary analysis of Study B, in which the decrease in GFR was correlated with the actual quantity of protein ingested, there was no effect of ingesting the LPD versus the very LPD supplemented with ketoacids and amino acids on the progression of renal failure (104). However, in Study A, when the data from the two groups were combined and then analyzed, there was a significant inverse relationship between the protein intake actually ingested, as determined from the urea nitrogen appearance (UNA) (see later), and the rate of decline in GFR (104). The actual dietary protein intake associated with the lowest rate of decline in GFR was about 0.62 g/kg/day. More recently, at least one other small-scale randomized controlled study compared treatment with a very-lowprotein, ketoacid-amino acid-supplemented diet to a 0.6 g/day protein diet in patients with CKD. The results indicated that the ketoacid diet was more effective at slowing progression of CKD (116).

The mechanism of action by which ketoacid diets retard progression of renal failure is unclear. Studies suggest that alkalinization of the urine can retard the progression of renal failure (117, 118, 119). Because ketoacids in the dietary supplements are present as alkaline salts, perhaps it is the alkali in these supplements that actually retards progression of renal failure, if the rate of progression is indeed slowed.

A 12-year follow-up analysis was conducted in the Study A MDRD patients concerning the hazard ratio, adjusted for baseline characteristics, of developing ESRD or a combination of either ESRD or all-cause mortality (120). ESRD was defined as commencing MD therapy
or receiving a kidney transplant. This study indicated that during the first 6 years after the onset of the dietary protein prescription, there was a statistically significant adjusted lower hazard ratio of incurring ESRD, or the combination of either ESRD or mortality in those assigned to the 0.60 g protein/kg/day diet versus those assigned to the 1.3 g protein/kg/day diet (120). This difference tended to reverse itself in the second 6-year period of follow-up.

In Study B patients, those assigned to the ketoacid supplemented diet had a significantly greater hazard ratio, adjusted for baseline factors, for death after they developed ESRD during the 12 years after assignment to their diet prescription (121). These data are particularly intriguing because patients were treated in the study, on average, only for the first 2.2 years of follow-up and were then referred back to their usual physicians. Moreover, with few exceptions, ketoacid mixtures were not available to patients in the United States after the MDRD Study ended. Thus, the Study B patients could not have taken ketoacids during most of this 12-year observation period. A rather large, retrospective study from France did not confirm any difference in long-term mortality rate in patients with CKD who are prescribed ketoacid diets (122). However, this study compared survival of these former patients with survival data from the French dialysis registry and with patients who underwent transplant procedures in Bordeaux. It is possible that the patients who agreed to take the ketoacid diets were a more motivated, capable, disciplined, and healthier group of individuals; and one could imagine that, all else equal, their survival rate should be greater than that of the average French dialysis patient.

The Nurses’ Health Study compared spontaneous protein intakes of individuals with different levels of GFR, determined from their serum creatinine concentrations (123). In this study, 1624 women, aged 42 to 68 years, had their protein intake measured in 1990 and again in 1994 using a semiquantitative food frequency questionnaire. Those women with mildly reduced baseline estimated GFR levels that were greater than 55 mL/minute/1.73 m2 but less than 80 mL/minute/1.73 m2 showed a fall in GFR of −1.69 mL/minute/1.73 m2 per 10-g increase in protein intake. However, after adjustment for measurement of error, the change in estimated GFR was −7.72 mL/minute/1.73 m2 per 10-g increase in protein intake. This association was of borderline statistical significance. A high intake of nondairy animal protein in people with mild renal insufficiency was associated with a significantly greater fall in estimated GFR (− 1.21 mL/minute/1.73 m2 per 10-g increase in nondairy animal protein intakes). A retrospective study in renal transplant recipients indicated that those recipients who spontaneously ingested higher protein diets experienced greater losses of GFR (124).

Taken together, the post hoc analysis of the MDRD Study data, the results of the approximately 12 years of follow-up to the MDRD Study, the Nurses’ Health Study, the study in renal transplant recipients, the four metaanalyses, and the newer randomized ketoacid studies all point to the probability that LPDs will retard the rate of progression of renal failure in individuals with CKD. Moreover, because these LPDs often engender sufficiently lower uremic toxicity for a given level of reduced renal function, patients fed these diets may be able to avoid MHD, CPD, or renal transplantation at GFR levels that would require individuals ingesting higher protein intakes to commence such therapy.

An interesting question is whether LPDs may prevent or retard the development of renal failure in individuals with no underlying renal disease. At the present time, there are no clear answers to this question.

Another unresolved issue is whether LPDs will retard progression of renal failure in patients receiving ACEIs and/or ARBs. Because dietary protein restriction exerts many of the same hemodynamic and other physiologic effects on the kidney as do ACEIs and ARBs (44, 45, 125), it is possible that the renal-protective effects of LPDs, when combined with ACEIs and ARBs, are replicative, rather than additive. In a rather small study, 82 patients with type 1 diabetes mellitus were randomly assigned to an LPD (0.60 g protein/kg/day) or a more usual-protein diet (126); most of the patients were receiving ACEIs. In this 4-year trial, the low-protein group experienced a 10% incidence of death or ESRD as compared with 27% in the patients eating the usual-protein diet (p < .042). There was no difference in the rate of decline in GFR in the 2 groups (126).

Because proteinuria is associated with greater progression of renal failure and increased risk of cardiovascular disease, and because ACEIs and ARBs, even in combination, and blood pressure lowering may reduce proteinuria but not eradicate it, there may be a role for LPDs at least in persistently proteinuric patients. More research in this area is clearly needed.


The nephrotic syndrome is a kidney disorder characterized by losses of large quantities of protein in the urine (>3.0 g/ day), low serum albumin concentrations, high serum levels of cholesterol and other fats, and accumulation of excess body water to form edema (127). This condition is caused by diseases that affect the glomerulus and increase glomerular permeability to protein. Because patients with the nephrotic syndrome have large urinary protein losses and their appetite is frequently poor, they often develop protein wasting and debility. Certain vitamins and most trace elements are protein bound in plasma, and these patients are therefore also at risk for developing deficiencies of these nutrients when these proteins are lost in the urine. Excessive urinary iron, copper, and vitamin D losses and vitamin D deficiency have been reported in patients
with the nephrotic syndrome (127, 128). Malnutrition may occur in nephrotic patients even when they do not have advanced kidney failure. For a given type of renal disease, heavy proteinuria is associated with more rapid progression of renal failure, possibly because of the incorporation of proteins into the glomerular mesangium that may cause sclerosis or inflammatory responses (129). Many growth factors and other bioactive substances are also bound to proteins that are filtered by the leaky glomerulus in patients with the nephrotic syndrome. It is postulated that some of these bioactive compounds, when filtered and exposed to the renal tubular lumen or renal interstitium, may promote progressive renal damage (130). As indicated earlier, protein-restricted diets, ACEIs, ARBs, and aldosterone receptor antagonists may each reduce renal losses of protein (131, 132, 133, 134). Using these medicines in nephrotic patients to reduce proteinuria while maintaining a sufficiently high protein intake to increase both albumin and total body protein mass may be desirable.


CRF causes pervasive nutritional and metabolic disorders that may affect virtually every organ system. These abnormalities are reviewed briefly.

Clinical, Nutritional, and Metabolic Disorders

Advanced CRF is a complex disorder caused by a marked reduction in the excretory, endocrine, and metabolic functions of the kidney. Patients with CRF eventually develop uremia, which refers to the accumulation of nitrogenous metabolites in the blood in combination with the clinical signs and symptoms of advanced renal failure. Most of these compounds are products of amino acid and protein metabolism. Quantitatively, the most prominent are urea, creatinine, other guanidine compounds and uric acid (Fig. 97.1). It is generally believed that some of these compounds are toxic in high concentrations.

The many signs and symptoms of uremia include weakness, a feeling of ill health, insomnia, fatigue, loss of appetite, nausea, vomiting, weight loss, diarrhea, itching, muscle cramps, hiccups, twitching or jerking of the extremities, fasciculations, tremors, emotional irritability, and decreased mental concentration and comprehension. A characteristic fetid breath, caused at least partly by exhalation of methylamines, is often present.

Altered serum concentrations of other electrolytes and acidemia (excessive accumulation of hydrogen ion in the blood) can occur and can have profound and life-threatening effects on the physiologic processes and metabolism of the body (see Fig. 97.1). Abnormalities in water and electrolyte balance and acidemia are caused by impaired ability of the failing kidney to regulate, by excretion, the content of water, salts, and acids in the body. The sodium and water disturbances associated with renal failure can lead to congestive heart failure and hypertension or, if excessive sodium depletion occurs, reduction in extracellular fluid volume and a fall in blood pressure. When renal failure is not in the end stage or nearly so, most of these clinical and metabolic disorders can be ameliorated or prevented with dietary and medicinal therapy. Untreated uremia can lead to lethargy, loss of consciousness, coma, convulsions, and death.

Fig. 97.1. Relationship between plasma urea nitrogen (PUN) and the glomerular filtration rate as indicated by urea clearance in Sprague-Dawley rats with chronic renal insufficiency and sham-operated controls. Chronic renal failure was produced by ligation of two thirds to three fourths of the arterial supply to the left kidney and contralateral nephrectomy. (Reprinted with permission from Kopple JD. Nutrition and the kidney. In: Alfin-Slater BB, Kritchevsky D, eds. Human Nutrition: A Comprehensive Treatise. Vol 4. New York: Plenum Publishing, 1979:409-57.)

Advanced CRF causes pervasive alterations in the absorption, excretion, or metabolism of many nutrients. These disorders include the following: accumulation of chemical products of protein metabolism (2), a decreased ability of the kidney either to excrete a large sodium load or to conserve sodium rigorously when dietary sodium is restricted (135); impaired renal ability to excrete water, potassium, calcium, magnesium, phosphorus, trace elements, acids, and other compounds; a tendency to retain phosphorus (136, 137, 138, 139, 140); decreased intestinal absorption of calcium (137) and possibly iron (140); and a high risk for developing certain vitamin deficiencies, particularly vitamin B6, vitamin C, folic acid, and the most potent known form of vitamin D, 1,25-dihydroxycholecalciferol (138, 141). The patient with CRF is also likely to accumulate certain potentially toxic chemicals, such as aluminum, that normally are ingested in small amounts and excreted in the urine (140).

Uremia is also a polyendocrinopathy, and many of the metabolic and clinical manifestations of uremia are caused
by the endocrine disorders. Many hormone concentrations are elevated in renal failure, particularly those of the peptide hormones, because of the impaired ability of the kidney to degrade peptides. These elevated peptide hormones include PTH, leptin, glucagon, insulin, growth hormone (GH), prolactin, luteinizing hormone, often follicle-stimulating hormone (FSH), and gastrin (137, 142, 143, 144, 145, 146, 147, 148, 149, 150). Increased secretion of some hormones, such as PTH and insulin, may contribute to elevated plasma levels. Patients with CRF have altered thyroid hormone levels that are similar to the euthyroid sick syndrome, but hypothyroidism is not common (151). Of the hormones elaborated by the kidney, plasma erythropoietin and 1,25-dihydroxycholecalciferol are reduced (5, 6, 7, 8, 138); and plasma renin activity may be increased, normal, or decreased.

Serum GH is elevated, and IGF-I levels are usually normal in renal failure, but there is resistance to the activity of both GH and IGF-I (152, 153). Sensitivity to glucagon is reversed by hemodialysis, although hyperglucagonemia persists (143). Resistance to the peripheral action of insulin occurs (154). These effects on insulin and glucagon contribute to the mild glucose intolerance usually present in nondiabetic patients with CRF (144). Obesity, which is common in patients with CKD, may contribute to glucose intolerance. Impaired actions of hormones in uremia may result from circulating inhibitors in serum, down-regulation of receptor number, or postreceptor defects in the signal transduction system. Cytosolic calcium participates in certain cell signaling systems. Elevated basal cytosolic calcium, induced by hyperparathyroidism, appears to be one of the postreceptor signal transduction disorders induced by CRF (155).

Most of the products of metabolism that accumulate in renal failure do so as the result of decreased excretion. The ability of the failing kidney to synthesize or metabolize many compounds, including amino acids, is also impaired. In CRF, the kidney displays reduced catabolism of glutamine, impaired synthesis of alanine, and decreased conversion of glycine to serine and citrulline to urea (156, 157). Serum and tissue taurine levels are often low.

Quantitatively, the most important end product of nitrogen metabolism is urea (158). In a clinically stable patient with CRF who eats at least 40 g of protein per day, the net quantity of urea produced each day contains an amount of nitrogen equal to about 80% to 90% of the daily nitrogen intake. Guanidines are the next most abundant end product of nitrogen metabolism. Guanidino compounds include creatinine, creatine, and guanidinosuccinic acid (2, 158). Many polypeptides and small proteins also accumulate in CRF (158). Most certainly, many compounds contribute to uremic toxicity. Prime suspects for uremic toxins include urea, guanidine compounds, phenolic acids, proinflammatory cytokines, carbonyl compounds, oxidants (see later), and some of the hormones elevated in uremic plasma, especially PTH and possibly glucagon (2, 143, 155, 158, 159, 160).

Altered gastrointestinal function may affect nitrogen metabolism in patients with CRF. The gastrointestinal tract metabolizes urea, uric acid, creatinine, and choline and synthesizes or releases from larger molecules dimethylamine, trimethylamine, ammonia, sarcosine, methylamine, and methylguanidine and certain tryptophan metabolites (158). The gut metabolism or synthesis of many of these compounds is increased in CRF, possibly because of the rise in the quantity of intestinal bacterial flora (161).

Some of the metabolic alterations in uremia are adaptive homeostatic responses that offer both benefits and disadvantages to the patient (159). Hyperparathyroidism is an example. As the kidneys fail, impaired excretion of phosphorus leads to phosphorus retention. Concomitantly, the diseased and scarred renal parenchyma is less able to convert 25-hydroxycholecalciferol to the most potent metabolite of vitamin D, 1,25-dihydroxycholecalciferol, a powerful suppressor of PTH secretion (138). Low plasma concentrations of 1,25-dihydroxycholecalciferol lead to an increase in PTH secretion.

In addition, deficiency of 1,25-dihydroxycholecalciferol both impairs intestinal calcium absorption and causes resistance to the actions of PTH in bone (137, 138). These alterations also promote hypocalcemia and contribute to the development of hyperparathyroidism. Elevated serum PTH reduces renal tubular reabsorption of phosphorus (enhancing urine phosphorus excretion), lowers serum phosphorus, promotes renal synthesis of 1,25-dihydroxycholecalciferol, mobilizes calcium from bone, and increases intestinal calcium absorption, although intestinal calcium absorption usually remains low or, in mild renal insufficiency, normal. The benefits derived from these homeostatic actions are that more normal concentrations of plasma phosphorus and calcium are maintained in patients with mild to more advanced renal insufficiency. The trade-off is the development of hyperparathyroidism (159, 160). PTH has been implicated as a pervasive uremic toxin that adversely affects many organs and tissues and contributes to the uremic syndrome (160). Fibroblast growth factor-23 (FGF23) is another hormone that regulates phosphorus homeostasis by reducing renal tubular phosphorus reabsorption and promoting urinary phosphorus excretion (139). Anemia, which usually is primarily, but not exclusively, the result of impaired erythropoiesis caused by deficiency of erythropoietin, can be treated effectively with this hormone (8). To reduce the risks of adverse events, including possibly higher mortality, and the high costs of therapy, sufficient erythropoietin is usually given to raise the hemoglobin levels only to the currently recommended levels of about 11 to 12 g/dL (162, 163). Large doses of iron are usually given intravenously to patients undergoing MD and orally or intravenously to patients with CKD, to attain a higher serum total iron binding saturation. Erythropoietin and other erythropoiesis-stimulating agents are expensive and, in large doses, possibly hazardous medications, and these higher serum iron levels will
often decrease the amount of these medications needed to maintain target hemoglobin levels (164).

When kidney failure is a complication of an underlying systemic disease, such as diabetes mellitus, hypertension, or lupus erythematosus, other manifestations of these underlying diseases may also adversely affect the patient and may be progressive. All of these problems do not seriously affect every patient, and many patients with CRF or who are undergoing dialysis lead full and productive lives.

With the institution of dietary therapy or treatment with MHD or CPD, blood levels of many metabolic products that accumulate in uremic plasma decrease, and the patient may experience clinical improvement. MHD or CPD enables patients to live for many years with essentially no renal function. Despite such improvement, however, many clinical and metabolic disorders may persist or even progress. These include the following: oxidative and carbonyl stress; an inflammatory state; type IV hyperlipidemia and other disorders of lipid metabolism (165, 166); a high incidence of cardiovascular, cerebrovascular, and peripheral vascular disease (167); osteodystrophy with disordered bone architecture, osteoporosis, or osteomalacia (aluminum toxicity often contributes to the osteomalacia) (137, 168); anemia (6, 7, 8); impaired immune function and decreased resistance to infection; mildly impaired peripheral and central nervous system function; muscle weakness and atrophy; frequent occurrence of viral hepatitis (169); sexual impotence and infertility; generalized protein-energy wasting (PEW) (170, 171, 172, 173, 174, 175, 176, 177, 178); a general feeling of ill health or emotional depression; and poor rehabilitation (179). Most of these complications can be aggravated by poor nutritional intake or improved with good nutrition.

The foregoing considerations indicate that the intestinal absorption, excretion, and/or metabolism of virtually every nutrient may be altered in CRF. In addition, the decreased intake of food and excessive intake of certain minerals, such as phosphorus, sodium, or potassium, may alter clinical or nutritional status. Moreover, medicinal therapy may adversely affect nutrient metabolism in renal failure. For example, anticonvulsant medications may cause deficiencies of vitamin D and folic acid; hydralazine, isoniazid, and other medications may cause vitamin B6 deficiency (180). Part of the challenge of dietary therapy for such patients is to provide for the altered requirements and tolerance of many nutrients that occur in CRF.

Protein-Energy Wasting

Patients with CRF, and particularly in those undergoing MHD or CPD, frequently show evidence of wasting and particularly PEW (see Table 97.2). The term PEW is used because not all causes of PEW are the result of inadequate nutrient intake (170, 171, 172, 173, 174, 175, 176, 177, 178, 181, 182).

Evidence for PEW includes decreased relative body weight (i.e., the patient’s body weight divided by the weight of physiologically normal people of the same age, height, sex, and skeletal frame size); body mass index (BMI); skinfold thickness (an estimate of total body fat); arm muscle mass; total body nitrogen and potassium; subjective global nutritional assessment (SGA); low growth rates in children; decreased serum concentrations of many proteins including albumin, transthyretin (prealbumin), and transferrin; and low muscle alkali-soluble protein. The plasma amino acid pattern, which is pathognomonic for renal failure, also has similarities to that found in malnutrition.

The findings of PEW are sometimes observed in nondialyzed patients with CRF, but they are more prevalent in patients undergoing MHD or CPD. Not every dialysistreated patient has evidence for these disorders; however, virtually every survey of patients undergoing MD indicates that these patients have an increased prevalence of PEW (170, 171, 172, 173, 174, 175, 176, 177, 178, 181). PEW is only mild to moderate in most dialyzed patients with this condition. About 6% to 8% of dialysis-treated patients have severe wasting. In addition to PEW, patients with CRF are at higher risk for malnutrition of iron, zinc, and certain vitamins, including vitamin B6, vitamin C, folic acid, 1,25-dihydroxycholecalciferol, and possibly carnitine and often other nutrients (183, 184, 185, 186, 187, 188).

There are many causes of wasting in CRF (Table 97.3) (171). First, dietary intake is often inadequate, particularly for energy requirements (170, 175, 189, 190). The low dietary intake is mainly the result of anorexia. This is caused by uremic toxicity, a CRF-related inflammatory state, the anorexigenic effects of acute or chronic superimposed illnesses, and emotional depression. Associated illnesses may also impair the patient’s physical ability to procure, ingest, or digest foods or to receive or use tube feeding. In addition, the dietary prescription in renal failure, which is low in protein and other nutrients and may be difficult to prepare or be unpalatable, can lead to low nutrient intakes.

Second, the superimposed illnesses that patients with CRF frequently sustain often induce a catabolic state (191, 192, 193). Third, the dialysis procedure itself may induce wasting. Hemodialysis and peritoneal dialysis removes free amino acids, peptides or bound amino acids (194, 195, 196, 197), water-soluble vitamins (141), proteins (with peritoneal dialysis and, to a much lesser extent, with hemodialysis) (195, 198), glucose (during hemodialysis with glucose-free dialysate) (199), and probably other bioactive compounds. Hemodialysis also increases net protein breakdown, especially by activating the complement cascade system and inducing release of catabolic cytokines (see later) (200, 201). Fourth, excessive accumulation of acid in blood (acidemia) engenders protein catabolism (202). Fifth, patients with CRF sustain blood losses. Because blood is a rich source of protein, these losses may contribute to protein depletion. The blood losses are caused by frequent blood drawing for laboratory testing, the common occurrence of occult gastrointestinal bleeding, and sequestration of blood in the hemodialyzer and blood tubing (203).

Other possible, but not well established, causes of wasting include the following: altered endocrine activity, particularly resistance to insulin (154), GH, and IGF-I (152, 153); hyperglucagonemia (143), hyperparathyroidism (137, 155, 159,
160), and possibly deficiency of 1,25-dihydroxycholecalciferol (137); endogenous uremic toxins; exogenous uremic toxins, such as aluminum; and loss of metabolic functions of the kidney. Because the kidney is a metabolic organ that synthesizes or degrades many biologically valuable compounds, including amino acids (156, 157), the loss of these activities in kidney failure could possibly disrupt the body’s metabolism and promote wasting.



Body Weight

Height (children)

Growth (children)

Body fat (skinfold thickness)

Fat free solids

Intracellular water

Muscle mass (midarm muscle circumference)

Total body potassium (nondialyzed patients)

Total body nitrogen (patients receiving chronic

peritoneal dialysis)

Total albumin mass, synthesis, and catabolism

Valine pools (nondialyzed patients)


Total protein





C3 activator





Total tryptophan



Valine/glycine ratio

Essential/nonessential ratio


Alkali-soluble protein

RNA/DNA ratio



Normal to increased



aPatients with chronic renal failure may have normal values for these parameters, but statistical comparisons indicate that the levels are often abnormal in these individuals.

Inflammation and Oxidant and Carbonyl Stress in Chronic Renal Failure and Patients Undergoing Maintenance Dialysis

Patients with CRF and those undergoing MD frequently show evidence of inflammation. This evidence includes increased serum levels of such acute phase proteins as C-reactive protein (CRP), serum amyloid A, and ceruloplasmin. Serum levels of negative acute phase proteins, including albumin, transferrin, transthyretin (prealbumin), and cholesterol-carrying lipoproteins may decrease not only as a result of PEW but also as a direct result of inflammation (190, 204, 205, 206, 207, 208, 209, 210). Most surveys suggest that serum CRP levels are increased in about 30% to 50% of US and European MHD-treated patients and perhaps lower in Asian MHD-treated patients (207). Serum proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and IL-6, are commonly elevated in patients with advanced CRF (207). In patients with advanced CRF and those receiving MD, there is also an accumulation in serum of compounds that cause oxidant or carbonyl stress (207, 211, 212). Oxidant stress refers to cellular injury caused by exposure of the cell to compounds that oxidize chemicals in the cell (211). Carbonyl stress refers to cellular injury caused by carboncontaining compounds that react with compounds in the cell (212). Homocysteine is such a carbonyl-reactive compound that is increased in serum in patients with CRF and MD treatment and that, when elevated, exerts several adverse effects on the vascular endothelium (213, 214, 215, 216, 217).

Causes of inflammation in individuals with CRF include comorbid illnesses, CRF (which itself leads to an increase in serum levels of several oxidants, reactive carbonyl compounds, and proinflammatory cytokines), oxidant and carbonyl stress, chronic low-grade infections (e.g., by chlamydia), and reaction to the vascular access prostheses that are necessary to perform hemodialysis, the hemodialyzer itself, the peritoneal dialysis catheter (for CPD-treated patients) and (for MHD- or CPD-treated patients) dialyzer tubing or impure dialysate (205, 206, 210, 218)

Why Are Protein-Energy Wasting and Inflammation of Great Concern to Nephrologists?

The current high interest in PEW and inflammation stems from the fact that measures of either of these two conditions are epidemiologically linked to increased risk of morbidity and mortality in patients undergoing MD (19, 209, 210, 211, 219). Markers of inflammation have been particularly linked to atherosclerosis and cardiovascular morbidity and mortality (206, 207, 208, 217). Moreover, laboratory research indicates that certain acute phase proteins, oxidants, reactive carbonyl compounds, and proinflammatory cytokines can be directly toxic to the endothelium. These compounds may cause inflammation, cellular proliferation, and increased matrix deposition in the endothelium with the formation of inflamed atherosclerotic plaques that are likely to rupture and increase the likelihood of myocardial infarction or stroke. The increased risk of morbidity and mortality in patients undergoing MD who have PEW and/or inflammation is of particular importance because the adjusted mortality rate for MD-treated patients in the United States is very high, approximately 21% to 22% per year (193). Hence, in a population that is already at high risk for morbidity and mortality, the identification of clinical characteristics that
demonstrate the presence of a subgroup of these individuals who are at even greater risk for these adverse outcomes is a cause for alarm. At the same time, it affords a potential opportunity to develop interventions that may improve such poor prognoses.

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Jul 27, 2016 | Posted by in PUBLIC HEALTH AND EPIDEMIOLOGY | Comments Off on Nutrition, Diet, and the Kidney1

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