Adherence to ketoacids/essential amino acids-supplemented low protein diets and new indications for patients with chronic kidney disease

Maintenance dialysis is a burden for the global health systems globally and is growing at an unprecedented rate. A recent analysis of the prevalence of end stage renal disease led to the conclusion that the prevalence of maintenance dialysis has grown more rapidly during the last two decades than predicted [1]. Efforts to delay the progression to end stage renal disease (ESRD) mainly rely on control of blood pressure and diabetes. Unfortunately, in many countries nephrologists generally do not examine CKD patients until dialysis is imminent and they have few options for delaying the time to dialysis. However, increasing the time until transition to dialysis therapy may improve patient’s quality of life and can reduce the financial strain on the healthcare system. Consequently, postponing dialysis initiation should receive a high priority in majority of patients with advanced CKD. In fact, there is evidence that many patients will be able to postpone the transition to dialysis, reportedly, more than 60 % of all CKD patients can experience a persistently low GFR (i.e., below 25 ml/min/1.73 m²) during the two years prior to initiation of dialysis [2, 3]. In short, there is opportunity to reduce the drivers of chronic kidney disease, including poorly controlled hypertension and decreased symptoms of uremia using a low protein diet supplemented with ketoanalogues in countries where these agents are available and including dietary salt restriction [4, 5]. In jurisdictions without approved ketoacids such as the United States or Canada, essential amino acids can be used instead. These strategies were concisely reviewed in 2013 [6], therefore this review will focus on evidence for efficacy that has become available since. In addition, it should be recalled that the currently available ketoanalogues (KA) preparations are marketed with other essential amino acids (EAA), which will be referred as KA/EAA below in text.

The general approach to treatment of patients with low or supplemented very low protein diets often results in a tug of war between the patient’s will to comply vs nutritional temptations and deeply rooted food habits. Consequently, doctors should consider that to attain good compliance it is advisable to set goals of adherence – the conscious decision of the patient to stick with a therapy – as a therapeutic goal. To overcome this often frustrating situation, Piccoli et al. [7] sought to identify factors that influence patient adherence. They investigated implementation of a simplified low-protein, KA/EAA supplemented diet as part of the routine work-up of CKD patients. Patients with CKD stages 4 to 5 or patients with CKD stage 3 and rapid progression and/or a refractory nephrotic syndrome were offered SLPD (0.6 g protein/kg/day). The endpoint was defined as at least six months of follow-up on the diet and the results were analysed by comparing demographic and health parameters among patients following the diet for less than one month vs. those who followed the restricted diet for up to six months. The results indicated that successful adherence was unpredictable a priori, as no medical or social parameters were identified as indicative of continuous adherence to the SLPD [7]. Renal nutrition education has also been reported to improve adherence to LPD in a Brazilian randomized controlled trial [8].

Another recent study [9] from the same group addressed the compliance issue in 185 patients given KA/EAA supplemented LPD (0.6 g protein/kg/day supplemented with 1 tablet per 10 kg BW/day) vs 122 patients prescribed a LPD with the same protein intake and commercially available protein-free food. Adherence was assessed from food questionnaires, 24 h urine urea collection and tablet counts. Patients who chose SLPD were younger and had significantly lower GFR values and higher levels of proteinuria. After six months, the median protein intake was 0.7 g/kg BW/d in both groups. Albumin and total protein levels were stable at six and twelve months. Of note, even after GFR fell below 15 ml/min, the diet was still followed by 59 % patients at six months and 32 % at twelve months. At one year, all patients had reduced their albuminuria and degree of acidemia. Interestingly the two low protein diets were comparable in cost. Thus, compared to an “early start” dialysis (i.e., when GFR is >10 ml/min), this dietary approach of an KA/EAA supplemented 0.6 g protein/kg/day diet resulted in substantial financial savings [10].

A landmark trial for the therapy with supplemented low protein diet by Garneata et al. has been recently published [11]. These investigators conducted a prospective, open, parallel, randomized controlled study comparing vegetarian VLPD (0.3 g/kg/day) supplemented with KA/EAA, 1 tablet/5 kg BW with LPD (0.6 g/kg/day) in non-diabetic patients with a stable eGFR below 30 ml/min/1.73 m². The study had a three-step enrolment procedure: patients were asked if they would be willing to follow a low protein diet, vegetarian if necessary; only those who were willing to do so were included into a three month run-in period with a low protein diet. 1,413 patients were assessed for eligibility and 42 % of them declined to consider a vegetarian diet. Dietary compliance was controlled monthly, and only patients who followed the diet were finally enrolled and followed for up to 18 months. In the run-in phase, another 44 % dropped out, mainly for non-adherence to the LPD. Thus only 14 % (207) of the patients initially eligible entered the intervention period. The primary composite endpoint was initiation of dialysis or a reduction in the initial eGFR by more than 50 %. The SVLPD resulted in a significant delay of time to dialysis: while only 13 % in the SVLPD group reached the primary endpoint, 42 % did in the non-supplemented LPD group. Mean time to event was longer in the SVLPD group with 57 (55–59) weeks vs 47 (43–50) weeks in the control group (p < 0.001). The decline in eGFR was slower in SVLPD group as compared to LPD with a median difference between groups of 3.2 [2.6–3.8] mL/min. At 15 months, only the SVLPD group experienced a significant reduction of serum urea (120 [84–132] vs 167 [136–273] mg/dL) and serum phosphorus (4.4 [4.1–4.8] vs 5.5 [4.3–6.9,] mg/dl) while serum calcium (4.5 [4.4–4.7] vs 3.9 (3.9–4.0), mg/dL) and serum bicarbonate increased significantly (23.9 [21.5–25.1] vs 17.3 [15.3–18.7] mEq/L). The adjusted “number needed to treat” (NNT) to avoid the primary composite endpoint was 4.0 (3.9–4.4). The adjusted NNT to avoid dialysis initiation was 22.4 (21.5–25.1), but decreased to 2.7 (2.6–3.1) when only patients with eGFR <20 mL/min were retained in analysis. No significant changes in nutritional status and no drug-related adverse reactions were noted. Elderly (>65 years) and young active patients (<45 years) seemed to more easily accept the dietary intervention. Strong family/social support and, being already vegan or vegetarian were also identified as supportive characteristics [11]. Thus, adherence to a SVLPD can be achieved only if a good selection strategy is made and test periods are performed. Overall however, only 30 % of the pre-selected patients correctly achieved the very low protein intake reduction.

Recent reports provide additional information that can be offered to advanced CKD patients, in order to help motivate them to adhere to these low and very low protein diets. These studies also provide additional evidence supporting the safety of these diets. Adherence to a protein-restricted diet can be improved by selecting patients and offering them tailored dietary choices. Taken together, these new research data confirm an overall picture that a low protein diet providing 0.3–0.6 g/kg BW/d with added KA/EAA supplements may improve proteinuria [27] and delays time until dialysis has to be started [28]. The latter most likely occurs because uremic toxicity is reduced.