Novel dietary interventions
Many of the deleterious effects of dietary protein are related to specific components of the diet. This has led to attempts to control such complications by selectively preventing the absorption of one or more dietary components. Theoretically, such an approach could retain the nutritional benefits of proper protein intake while avoiding its undesirable side effects (Table 1).
Phosphorus is present in many dietary proteins. It has numerous adverse effects, including direct vascular toxicity and an association with increased mortality and progression of CKD,27 and the application of phosphorus binders in patients with non-dialysis dependent CKD has been associated with lower mortality in observational studies.28
Small clinical trials in patients with CKD29 and in laboratory animals30 showed an attenuation of CKD progression after dietary restriction of phosphorus. These studies would need to be corroborated by larger clinical trials before phosphorus binders can be recommended towards treatment of progressive CKD or to decrease mortality.
Potassium is also introduced through intestinal absorption (albeit not necessarily with proteins), and abnormally high or low levels have been associated with increased mortality in CKD and ESRD,31,32 and hypokalemia has also been associated with significantly more severe loss of kidney function.32
Dietary interventions can thus be used to avoid both high and low serum potassium levels with a goal towards improving both renal outcomes and survival. Interventions such as dietary modifications, medical potassium supplementation or the use of potassium binders are widely applied in everyday practice due to the accepted arrhythmogenicity of both hypo- and hyperkalemia.
It is thus unlikely that randomized controlled trials will ever be conducted to test the clinical utility of such interventions towards other endpoints; thus, their potential benefits in these regards will likely remain theoretical.
Metabolic acidosis is another frequent metabolic abnormality in CKD and ESRD that can be linked to nutrition and to the amount of protein intake. Its adverse effects are complex and include protein catabolism and PEW,33 worsening uremic bone disease,34 an association with increased mortality in patients with ESRD,35 non-dialysis dependent CKD,36 kidney damage, and increased progression of CKD.37
Bicarbonate supplementation has been shown to be renoprotective in a number of small single center randomized clinical trials,38;39 and alkali-rich diets such as vegetarian diets administered to CKD patients have been shown to decrease proteinuria40 and serum levels of phosphorus, parathyroid hormone, and fibroblast growth factor-23.41
The impact of therapies for metabolic acidosis on clinical outcomes will also have to be tested in larger clinical trials, but the ease of administration, the relative lack of side effects (provided that metabolic alkalosis is prevented), and the low cost of these interventions make it a desirable therapeutic target that can be pursued even while awaiting final evidence about its efficacy.
Other uremic toxins
Indoles and phenols are other potential uremic toxins linked directly or indirectly to intestinal absorption. These are products of protein catabolism in the gut that have been shown to cause oxidative stress, inflammation, vascular and renal toxicity, and increased mortality.42
One of the most frequently studied protein catabolic by-products is indoxyl sulfate, which has also been linked to kidney damage and progression of CKD.43 Binder medications that can lower the absorption and the systemic levels of indoxyl syulfate (such as AST-120) have been shown to ameliorate renal interstitial fibrosis, glomerular sclerosis, and proteinuria43 in animal models. Human benefits have been suggested in small randomized controlled trials.44,45
Unfortunately, similar benefits were not corroborated by larger clinical trials such as the EPPIC-1 and EPPIC-2 studies (ClinicalTrial.gov study numbers: NCT00500682 and NCT00501046). Exploratory analyses indicated that certain subgroups of patients (such as those at high risk for progression and those unable to strictly adhere to the medication regimen) may derive a significant renoprotective benefit from this intervention, but this would have to be corroborated in future studies.
The type and amount of ingested protein affects clinical outcomes such as PEW, kidney function, and even survival, and various dietary interventions have emerged as a means to attempt improving these outcomes. Protein restriction may be effective, but its implementation on a large scale in clinical practice is difficult.
Other interventions such as protein supplementation, the use of binder medications to affect intestinal absorption of phosphorus or various protein catabolic products, potassium supplementation, or correction of metabolic acidosis are all possible interventions that could be beneficial for different indications.
With the exception of protein restriction (including low protein diets and supplemented very low protein diets), the clinical trial evidence for many of these interventions is sparse or non-existent, so their wide-scale implementation in clinical practice cannot yet be recommended.
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