Dietary protein restriction
Reduction in dietary protein intake can have a variety of positive effects in the uremic patient, including the alleviation of uremic symptoms, control of hyperparathyroidism, hyperphosphatemia, and hyperkalemia, favorable glomerular hemodynamic effects, and a reduction of proteinuria.1
Based on these putative benefits, the Modification of Diet in Renal Disease (MDRD) study was designed to test the hypothesis that a low or very low protein diet can favorably affect the course of kidney disease in non-diabetic patients with moderate and advanced CKD. The primary results of the MDRD study showed no significant effect of the interventions on the slopes of measured GFR, although patients who received the supplemented very low protein intake had a marginally favorable outcome (p=0.07).2
Secondary analyses indicated that the early hemodynamic effects of protein restriction may have affected the overall results because patients receiving lower protein intake had significantly more loss of kidney function in the first four months of the intervention and significantly less loss of kidney function thereafter, resulting in an aggregate null effect. This suggests that perhaps a longer follow-up would have demonstrated a beneficial effect of protein restriction.3
A subsequent meta-analysis that incorporated data from 10 randomized controlled studies in 2,000 non-diabetic patients with moderate and advanced CKD suggested that a low protein diet (defined in general as a daily protein intake of 0.6 g/kg/day) resulted in a 32% lower incidence of dialysis, death, or renal transplant. To avoid one renal death, 2 to 52 patients needed to be treated with low protein intake over one year.4 These meta-analyses suggest benefits from protein restriction in terms of slowing progression of CKD.
The practical implementation of low protein diet-based strategies has been hampered by a variety of factors (Table 1). One potential reason relates to concerns about inducing PEW and engendering increased mortality.5 While a properly implemented low protein diet is not likely to cause PEW, proper implementation of such a diet can be difficult.
It requires substantial healthcare resources and significant motivation and possibly financial sacrifices on the part of patients. Insufficient energy intake is a common reason why low protein diets may lead to the development of PEW. Consumption of primarily low biological value proteins with the low protein diet (due to greater convenience or to better palatability of foods containing low quality protein) can also increase the risk of negative protein balance and consequent PEW.
Supplemented low and very low protein diets
As mentioned above, restricting protein intake in a proper manner (i.e., to achieve both a pre-set low amount of high biological quality protein intake while also assuring normal energy intake) can be difficult, in part due to the complexity and individual variety of everyday diets.
One way to address these difficulties is to substitute a portion of the dietary protein intake with a prescribed supplement of high quality protein or protein equivalent (such as a mixture of essential amino acids, ketoacids, or both). With such a strategy a low total protein intake (e.g., 0.6 g/kg/day) can be achieved by restricting dietary protein intake to a very low amount (e.g., 0.3 g/kg/day) and providing the difference in the form of a prescribed supplement, hence the term “supplemented very low protein diet (SVLPD).”
Such a strategy offers a number of advantages (Table 1): It allows for a more precise administration of a set amount of protein intake, it assures the intake of proper high biological value protein, it offers more flexibility and palatability in dietary choices (since there is less concern about the quality of the dietary component), it carries a low catabolic burden,6 and it is easier to assure adequate energy intake.
A supplemented very low protein intake was used in Study B of the above-mentioned MDRD study.2 While the results of the MDRD study2 and a secondary analysis7 did not suggest a benefit from this strategy, it is possible that the type of supplement used in the MDRD study was not ideal, as it contained excessive amounts of tryptophan, which could have led to production of nephrotoxic metabolites.8
Subsequently, several smaller studies have examined the effect of supplemented very low protein diets on kidney function, and found to decrease proteinuria9 and result in less severe progression of CKD.1,10,11 SVLPD is considered generally safe based on the results of observational studies or post-hoc analyses of interventional studies,12-17 but this would have to be established definitively in dedicated clinical trials before their widespread application can be advocated.
The advantages of SVLPD can be conceptually extended to clinical scenarios where protein intake does not need to be restricted or where it needs to be increased (see following section). By changing the amounts of the dietary component, the supplement component, or both, a total daily protein intake of any amount can be achieved while concomitantly maintaining control over the biological quality of the ingested proteins, the amount of daily energy intake, and minimizing the deleterious effects of excess protein intake.