Current Uses of Dietary Therapy for Patients with Far-Advanced CKD

Abstract

For several decades, inquiry concerning dietary therapy for nondialyzed patients with CKD has focused mainly on its capability to retard progression of CKD. However, several studies published in recent years indicate that, independent of whether diet can delay progression of CKD, well designed low-protein diets may provide a number of benefits for people with advanced CKD who are close to requiring or actually in need of RRT. Dietary therapy may both maintain good nutritional status and safely delay the need for chronic dialysis in such patients, offering the possibility of improving quality of life and reducing health care costs. With the growing interest in incremental dialysis, dietary therapy may enable lower doses of dialysis to be safely and effectively used, even as GFR continues to decrease. Such combinations of dietary and incremental dialysis therapy might slow the rate of loss of residual GFR, possibly reduce mortality in patients with advanced CKD, improve quality of life, and also, reduce health care costs. The amount of evidence that supports these possibilities is limited, and more well designed, randomized clinical trials are clearly indicated.

Introduction

Although large numbers of studies have examined dietary therapy for patients with CKD (1–3), the role for this treatment remains controversial (4). Traditionally, two major indications for dietary therapy for patients with CKD have been proposed. One indication is to reduce damage to the kidney, thereby decreasing progressive kidney injury and scarring, and reduce the rate of progressive loss of kidney function (5). This treatment is particularly focused on the role of dietary protein and phosphorus restriction in slow progression of CKD (5). The other indication is to reduce the accumulation of potentially toxic compounds in patients with CKD and also, prevent or treat protein-energy wasting (6,7). The relative interest in these two potential roles for treatment of CKD has varied greatly, at least since the 19th century (8). From the mid-1950s until about the mid-1970s, the focus of dietary therapy was primarily to reduce the accumulation of uremic toxins while preventing malnutrition (7). In the mid-1970s, Walser (5) reported that very low–protein diets (LPDs) supplemented with mixtures of some essential amino acids and ketoacid and hydroxyacid analogs of other essential amino acids (supplemented very low–protein diets [SVLPDs]) seemed to slow the rate of loss of GFR in patients with CKD. These observations engendered a reorientation among health care workers regarding their dietary treatment of patients with CKD, with a greater focus on the use of diet to retard the rate of progression of CKD.

Most studies have used two types of protein-restricted diets. Some workers recommend LPDs that provide 0.6–0.8 g protein/kg body wt per day for nondialyzed patients with advanced CKD (9). A 0.6-g protein/kg per day diet is nutritionally adequate for almost all non-nephrotic, nonhypercatabolic patients with CKD and will generate fewer potentially toxic products of protein metabolism than higher protein intakes (10). The 0.6-g protein/kg per day diet is less well tolerated by many patients than the 0.8-g protein/kg per day diet, and it may be more difficult for some patients to maintain an adequate energy intake with this former diet. For these latter individuals, the protein intake may be increased as necessary up to 0.8 g protein/kg per day. Where ketoacid or essential amino acid supplements are available, an SVLPD may be used. As currently used for nondialyzed patients with CKD, SVLPDs generally provide about 0.3–0.4 g protein/kg body wt per day supplemented with about 7–15 g mixture of ketoacid or hydroxyacid analogs of about five essential amino acids. Added to this are the other four essential amino acids (tryptophan, histidine, threonine, and lysine) and sometimes, one nonessential amino acid (1,11,12). Vegetarian foods are often the source of dietary protein, and protein-free foods may be added to ensure an adequate energy intake.

Many investigators have attempted to confirm the observations of Walser (5). Some investigators have used the foregoing SVLPDs; some have used SVLPDs with only the nine essential amino acids, and others have used LPDs providing about 0.6 g primarily high biologic value protein/kg per day. Whereas some studies, including several recent ones, suggest that LPDs or SVLPDs will retard the rate of progression of CKD (13), other studies, particularly the larger ones, have not confirmed these findings or at most, show a very modest degree of slowing of progression (1,14,15). More recently, ketoacid and essential amino acid supplements have been used with diets providing 0.60 g protein/kg per day; these latter diets generally have been used for patients undergoing chronic dialysis treatments (16).

The Controversy Concerning Dietary Therapy for Patients with CKD

Despite the widespread interest in transition of care from advanced CKD to RRT, many nephrologists, perhaps particularly in the United States, Europe, and Japan, currently prescribe little or no dietary treatment for patients with CKD (17). This seems to be true even for patients with stage 4 or 5 CKD, except that they might be referred to a dietitian. The arguments against dietary therapy for such patients can be summarized as follows (Table 1). Scientific evidence does not unequivocally show that LPDs retard progression of CKD (1–3,14,15). Other treatments, such as BP control (18), inhibition of the renin-angiotensin-aldosterone system (19), provision of alkali (20) or prevention of acidosis (21), and therapy for specific kidney diseases, do slow progression. For most people, dietary therapy is difficult to follow and is not pleasant (22). Dialysis is readily available and often free for virtually all people in the wealthier countries of the world (23). It is possible that financial incentives to start dialysis earlier; the ready availability of trained chronic dialysis teams of nurses, dietitians, social workers, and technicians; and the preexisting comprehensive treatment protocols in chronic dialysis centers may provide disincentives for busy physicians to spend the time necessary to treat patients with advanced CKD with conservative nondialysis dietary therapy.

Table 1.

Why dietary therapy for patients with CKD may not be prescribed more frequently by nephrologists

Factors	Explanation
Acceptance/adherence	Patients often do not enjoy or tolerate dietary therapy, and adherence to such diets is often low (22)
Efficacy	The effectiveness of LPDs and SVLPDs for retarding progression of CKD is controversial (4,15)
Concerns about safety	There are concerns as to whether LPDs or SVLPDs may engender protein-energy wasting; such concerns are not justified if diets are well designed (7)
Limited knowledge	Nephrologists are often unfamiliar with the optimal intakes of protein and other nutrients and the CKD stage at which they should be prescribed
Time consuming and laborious	Detailed discussions about dietary prescription and close monitoring of the patient’s condition are often necessary; this can be time consuming and laborious, particularly in comparison with commencing dialysis

LPD, low-protein diet; SVLPD, ketoacid- and essential amino acid–supplemented very low–protein diet.

Aside from whether SVLPDs or LPDs retard progression of CKD (5,15), there are other compelling reasons for using dietary therapy when a patient’s GFR decreases to 10–20 ml/min and especially, when it decreases below 10 ml/min (Table 2). Such patients often retain sodium, potassium, phosphorus, acids, and water. Excess body sodium is associated with increased oxidative stress (24). Sodium and water retention are associated with edema, heart failure, and early mortality (25). Hyperkalemia increases the risk of mortality (26). Hyperphosphatemia is associated with increased coronary artery calcification (27), hyperparathyroidism, and greater mortality (28); hydrogen ion retention leads to metabolic acidosis. Even in the general population, people with serum phosphorus levels in the upper range of normal show an increased incidence of cardiovascular events (29).

Table 2.

Potential benefits of dietary therapy for patients with far-advanced stage 5 CKD

Potential Benefits	Explanation
Delay CKD progression	Effectiveness remains controversial (2,15)
Reduce uremic toxicity	Avoid excess body burden of water and minerals: water, sodium, potassium, phosphorus, magnesium, trace elements (e.g., aluminum, copper) (24,26,27)
	Decrease accumulation of metabolites from proteins, peptides, amino acids, adenines, lipids, or carbohydrates (e.g., hydrogen ion, guanidines, phenols, indoxyl compounds, advanced glycated products) (30,31,33)
Prevent malnutrition	Maintain sufficient energy intake of energy, calcium, trace elements (e.g., iron, zinc, selenium), and vitamins (especially vitamin B6 [pyridoxine], folate, vitamin C, cholecalciferol, and 1,25-dihydroxycholecalciferol) (7,10,38–41,46)
Improve quality of life	By postponing dialysis therapy
Use incremental or infrequent dialysis	By reducing generation and accumulation of uremic solutes and water (50,52)
Other health benefits	May delay dialysis treatment until maturation of vascular access, thereby avoiding the need for insertion of temporary vascular access catheters (47)

Moreover, the metabolism of protein and amino acids generates a large number of metabolites, a number of which are almost certainly toxic. These toxins include hydrogen ion (30), guanidines (31), phenols (32), indoxyl compounds (33), microglobulins, and advanced glycation end products (34). The generation of many of these products is reduced by restriction of dietary protein intake (30,31,33). Some of these potential toxins are produced by the micro-organisms in the gastrointestinal tract. Thus, dietary therapy may enable patients to safely delay the need for dialysis therapy by preventing or mitigating uremic toxicity. Dietary protein restriction in patients with advanced CKD can reduce uremic symptoms (6); maintain healthier body or extracellular concentrations of many minerals and compounds, including sodium, potassium, calcium, magnesium, phosphorus, and acid (30,35); and decrease insulin resistance (36).

Indeed, this may explain the seeming discrepancy, wherein several meta-analyses of randomized, prospective trials of LPDs or SVLPDs for patients with CKD indicate that LPDs and SVLPDs delay the composite outcome of death or the onset of RRT (2,37). However, the one meta-analysis examining diets and the rate of loss of GFR showed that LPDs and SVLPDs significantly slow the fall in GFR in patients with CKD but only by 0.53 ml/min per year (15). A likely explanation for this discrepancy is that LPDs and SVLPDs reduce the loss of GFR only slightly but have a greater effect on delaying chronic dialysis therapy, because they also reduce the generation of uremic toxins. Hence, for a given low-GFR level, the patients ingesting these diets are less uremic and less likely to be started on chronic dialysis treatment.

Benefits and Safety of Diets for Deferring Dialysis by Ameliorating Uremia

Patients with advanced CKD often ingest too little of certain nutrients as well as too much of others (Table 2). Many studies show that dietary energy intake is below nutritional needs of patients with advanced CKD (38). Intake of certain vitamins often is inadequate for patient needs (39); this seems to be particularly true for vitamin B6 (pyridoxine) (40), vitamin C, folate (38), vitamin D₃ or D₂ (41), and in some circumstances, 1,25-dihydroxycholecalciferol (41). Of relevance, a retrospective analysis of the China Stroke Primary Prevention Trial showed that hypertensive patients with CKD given enalapril (10 mg/d) plus folic acid (0.8 mg/d) had 21% slower progression of CKD than similar patients given enalapril (10 mg/d) alone (42). The risk of inadequate dietary vitamin B6 intake is accentuated, because the nutritional requirement for this vitamin is increased in advanced CKD (40). The nutritional need for supplemental iron is well established. There may also be a need for supplemental zinc (38) and possibly, other trace elements.

Inadequate nutritional intake in patients with advanced CKD is of substantial concern, because protein-energy wasting is common in patients who are beginning dialysis therapy (43). In the authors’ experience, patients often describe weight loss during the 3–6 months preceding their commencement of chronic dialysis therapy, a finding similar to that reported in nursing home patients starting dialysis (44). Tortorici et al. observed a decrease in serum albumin during the months before patients with advanced CKD began chronic dialysis (A. Tortorici, et al., unpublished data). These findings are troubling, because patients starting chronic dialysis who have protein-energy wasting have increased mortality (43). However, substantial data indicate that LPDs and SVLPDs, when properly prescribed, do not engender protein-energy wasting (7,10). These findings raise the possibility that properly prescribed dietary therapy in patients approaching ESRD might reduce their mortality risk after they commence chronic dialysis treatment, a thesis that would seem to be well worth testing (45,46).

The foregoing considerations suggest that LPDs or ketoacid or essential amino acid SVLPDs may be able to safely delay the need for chronic dialysis therapy by reducing the generation of uremic toxins, independent of whether the rate of decline of GFR is diminished. The clinical trial of Brunori et al. (12) is pertinent in this regard. These investigators showed that SVLPDs could safely delay dialysis initiation in patients with advanced CKD without diabetes who were older than 70 years old. Patients with GFR (mean of 24-hour creatinine and urea clearances) of 5–7 ml/min per 1.73 m² (mean =6 ml/min per 1.73 m²) were randomized to two groups of 56 patients each. One group started chronic hemodialysis or peritoneal dialysis soon after randomization, whereas the other group was treated with SVLPDs and started on dialysis treatment when they developed manifestations of ESRD that were not controlled with diet. In the patients assigned to SVLPDs, dialysis initiation was delayed by a median of 10.7 months, with no evidence of worse outcomes in comparison with those of the other group. Eventually, 40 (71%) patients of SVLPDs started chronic dialysis after 6–20 months because of fluid overload or hyperkalemia.

Unadjusted survival was not different between the two groups, although after adjustment for the greater age and somewhat higher prevalence of cerebral vasculopathy in the SVLPD group, there was significantly greater survival in the diet group by per-protocol analysis but not by intention to treat analysis. The number of hospitalizations and days of hospitalization per patient-year were significantly less (P<0.001 and P=0.02, respectively) in the SVLPD group, although these differences disappeared if hospitalizations for placement of the first dialysis access in the diet group were included in these calculations. These findings strongly suggest that dietary therapy can be used to safely delay (for up to several months) the need for chronic dialysis in selected patients with pre-ESRD. LPDs or SVLPDs may also provide patients with advanced CKD with sufficient time for placement and maturation of a permanent hemodialysis vascular access or peritoneal dialysis catheter without requiring the use of temporary catheters needed to inaugurate dialysis urgently (47). Mortality increases when people commence chronic dialysis (25). Functionality decreases in nursing home residents when they begin dialysis (48). If these adverse events are related to dialysis treatment per se, this may provide another indication for the use of LPDs and SVLPDs to delay the initiation of dialysis. More randomized, prospective clinical trials (RCTs) are needed to define the roles of dietary therapy for people with far-advanced CKD.

Dietary Therapy for Incremental or Infrequent Dialysis

Incremental or infrequent dialysis may offer another role for LPD and SVLPD therapy for patients with advanced CKD (Table 3). These dialysis regimens may be used for patients with advanced CKD whose GFR is so low that chronic dialysis is required but is sufficiently high that standard thrice-weekly hemodialysis or daily peritoneal dialysis may not be necessary to minimize uremia (49). A low dose of dialysis may be started in these patients (for example, providing hemodialysis once or twice weekly or giving a similarly reduced dose of chronic peritoneal dialysis). With incremental dialysis, as residual renal function (RRF; i.e., the patient’s remaining GFR) continues to decrease in these patients, the dose of chronic dialysis is progressively increased until the patient is receiving standard doses of dialysis therapy. In practice, many nephrologists simply use infrequent dialysis, wherein the patient receives a rather fixed dose of infrequent dialysis until RRF declines to a degree that standard dialysis therapy is instituted.

Table 3.

Potential advantages and disadvantages of incremental hemodialysis with low-protein diets and very low–protein diets

Advantages	Disadvantages
Better maintain residual renal function (51,52,56,57)	Require repeated measurements of residual renal function (49)
Allows patients more time to prepare for standard chronic dialysis therapy	Patients may not tolerate low- or supplemented very low–protein diets (50)
May be associated with increased survival (51)
Help train patients in the precepts of self-care
May maintain good nutritional and metabolic status (52)
Decrease costs of dialysis treatments (49,52)

Clinical trials and epidemiologic studies suggest that this treatment may offer several advantages to the patient. Patients seem to have their uremic symptoms mitigated as much as patients receiving standard dialysis therapy (49). Patients may find the treatment regimen preferable to a more demanding standard full-dose regimen of chronic dialysis therapy. Incremental or infrequent dialysis may allow patients needed time to arrange their lifestyle appropriately or become more emotionally adjusted to chronic dialysis therapy (50). Lower or less frequent doses of dialysis seem to delay the decline in residual GFR, improve quality of life, possibly decrease mortality rates, and reduce health care costs (49–53). In fact, higher levels of RRF are associated with reduced mortality rates in patients on chronic peritoneal dialysis and patients on chronic hemodialysis (54,55). A recent epidemiologic study indicated that, compared with patients treated with standard thrice-weekly hemodialysis, patients with renal urea clearance >3.0 ml/min per 1.73 m² may survive longer on once-weekly dialysis with slower loss of RRF, but those with renal urea clearance ≤3.0 ml/min per 1.73 m² may have greater mortality (51).

Because well designed LPDs and SVLPDs will reduce the load of many potentially toxic solutes that accumulate in kidney failure, the combination of incremental dialysis and dietary therapy may be particularly helpful for enabling patients with ESRD and substantial remaining RRF to safely delay standard dialysis therapy. Indeed, some investigators have combined once-or twice-weekly dialysis with well defined dietary management LPDs or SVLPDs (50,52,56,57). Their experience indicates that some but not all patients treated with this regimen are able to safely delay the need for standard dialysis treatment. Although hemodialysis may cause catabolic, inflammatory, and hemodynamic stresses, LPDs and SVLPDs seem to maintain good protein-energy and metabolic and clinical status and have slower loss of RRF (52,56,57), possibly because hemodialysis is performed less frequently. Strongly motivated patients who are more knowledgeable about CKD seem to adjust better to this diet and infrequent dialysis regimen (50,52).

The extent to which these apparent benefits of incremental or infrequent dialysis are due to or require the LPDs or SVLPDs that are not uncommonly prescribed with these dialysis regimens is not known. Indeed, there are no RCTs that compare outcomes with either incremental or infrequent dialysis with those of standard thrice-weekly hemodialysis or that compare incremental dialysis with LPDs or SLVPDs with incremental dialysis without such diets. RCTs are needed to confirm whether incremental or infrequent dialysis does induce these benefits and the degree to which LPDs or SVLPDs contribute to the apparent benefits of less frequent dialysis. In some studies of incremental dialysis, the frequency or dose of dialysis was not increased as the GFR continued to fall, and this latter type of treatment should probably be considered to be infrequent dialysis rather than incremental dialysis.

Future Directions

The patients with CKD who are more likely to benefit from LPDs and SVLPDs and the level of reduced GFR at which these diets should be implemented need to be better defined. RCTs should help in this regard. One approach would be to prescribe these diets when it is considered time to start maintenance dialysis therapy, although the authors believe that a strong case can be made to start some form of dietary therapy at substantially higher GFRs. This is particularly the case to control sodium, potassium, phosphorus, and calcium balance and maintain adequate energy intake so as to prevent protein-energy wasting. Protein restriction at higher levels of GFR may also ameliorate more subtle uremic symptoms. Current data suggest that patients need a minimum GFR level—possibly a urea clearance ≥2–3 ml/min per 1.73 m²—to do well with dietary therapy (46). Patients being considered for dietary therapy probably should not suffer from severe acute or chronic catabolic illness, should be able to understand the dietary therapy, should have self-discipline, and should be strongly motivated. This review does not address the question of whether dietary therapy can retard the progression of kidney failure.

We need a clearer understanding of the extent to which dietary therapy will maintain patients with pre-ESRD and patients with ESRD in good nutritional and metabolic status, safely prevent and ameliorate various manifestations of uremia, and thereby, delay the need for RRT independent of any effect on the rate of decline of GFR. The optimal intake of protein, amino acids, and other needed nutrients for these patients needs more careful definition. The role of LPDs and SVLPDs for patients receiving incremental or infrequent dialysis requires more investigation, particularly with regard to defining patients who are good candidates for such treatment, optimal dietary therapies for this regimen, and techniques for increasing dialysis treatment as RRF declines. Whether intestinal sorbents or binders (e.g., activated charcoal to bind indoxyl sulfate) can safely and effectively augment or replace dietary management also needs investigation (33).

Another challenge is improving the patient’s adherence to dietary therapy. Aparicio et al. (58) observed that about 50% of patients with CKD adhere satisfactorily to SVLPDs. This may be an overly optimistic estimate for the general CKD population, perhaps due to the types of patients referred to Aparicio et al. (58) and their clinical expertise. However, for the patient with pre-ESRD and the patient with ESRD, the prospect of commencing chronic dialysis therapy or undergoing more frequent (i.e., standard dose) dialysis often engenders much anxiety, which may increase the patients’ motivation for dietary adherence. Clearly, not every patient with CKD will adhere to LPDs or SVLPDs.

Finally, it would be helpful to improve the training of nephrologists concerning the nutritional management of CKD and the recognition by nephrologists that some dietary therapies can benefit patients with CKD. The ease with which nephrologists can provide nutritional therapy might be facilitated. The National Health and Nutrition Examination Survey (NHANES) data indicate that American men and women with stage 4 or 5 CKD have mean protein intakes of 1.03 and 0.99 g protein/kg ideal body wt per day, respectively, which is substantially greater than currently recommended intakes (59). This probably reflects, in part, the reluctance of nephrologists to prescribe protein restriction. One solution for this reticence might be to develop centers of excellence for nutritional therapy staffed by renal dietitians. Physicians could easily and with minimal effort refer patients with stage 4 or 5 CKD to these centers. Such centers could be economically feasible, at least in urban areas with larger population densities. Clearly, more research is required to examine these possibilities and clarify the potential uses of nutritional therapy for patients with far-advanced CKD.

Disclosures

N.H. received lecture fees from Kyowa Hakko Kirin Co., Ltd. (Tokyo, Japan) and Bayer Yakuhin, Ltd (Osaka, Japan). B.T.L. has no financial disclosures. J.D.K. has received consultation fees or other support from Nephroceuticals (Miamisburg, OH), Fresenius Kabi AG (Bad Homburg, Germany), Shire Pharmaceuticals (Dublin, Ireland), Abbott Nutrition (Columbus, OH), and Chugai Pharmaceuticals Co., Ltd (Tokyo, Japan).