Optimizing Diet to Slow CKD Progression

Due to the unique role of the kidney in the metabolism of nutrients, patients with chronic kidney disease (CKD) lose the ability to excrete solutes and maintain homeostasis. Nutrient intake modifications and monitoring of nutritional status in this population becomes critical, since it can affect important health outcomes, including progression to kidney failure, quality of life, morbidity, and mortality. Although there are multiple hemodynamic and metabolic factors involved in the progression and prognosis of CKD, nutritional interventions are a central component of the care of patients with non-dialysis CKD (ND-CKD) and of the prevention of overweight and possible protein energy-wasting. Here, we review the reno-protective effects of diet in adults with ND-CKD stages 3–5, including transplant patients.


INTRODUCTION
Advanced chronic kidney disease (CKD) is a systemic disorder which is associated with high mortality and poor quality of life. Different treatments and lifestyle modifications are needed to avoid progression to kidney failure, which requires of kidney replacement therapy (maintenance dialysis or transplantation), and exceedingly costly therapy to Society (1)(2)(3). Chronic kidney disease progression is largely conditioned by hemodynamic and metabolic factors independent of the primary kidney disease, many of them, such as the high blood pressure (BP), the hyperfiltration, or the proteinuria are highly influenced by diet (4). Moreover, due to the kidney's unique role in nutrient metabolism, patients with advanced CKD are unable to maintain adequate nutrient homeostasis, developing metabolic disorders as sodium and volume overload, hyperkalemia, hyperphosphatemia, metabolic acidosis, altered hormone regulation, and inflammation. Accordingly, nutritional interventions should be a fundamental strategy in the treatment of patients with CKD (5)(6)(7).
In recent years, several studies, trials, and meta-analyses have evidenced the effectiveness of protein restriction and others nutritional interventions on kidney outcomes (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). This evidence was judged to increase the strength of recommendations for the nutritional management of patients with CKD in the 2020 update of the KDOQI guidelines (18). In this review, we aim to summarize recent studies on the role of diet, focusing on salt and protein restriction, as well as the use of supplements with essential amino acids (AAs) and keto analogs (KAs) to delay the progression of CKD and, at the same time, to preserve the nutritional status of patients with ND-CKD.  (18). being fruits and vegetables an alternative to oral alkali that may reduce the risk for volume retention and/or hypertension related to bicarbonate supplementation (28). Given the role of calcium balance and the serum phosphate in the development of cardiovascular calcifications, several experts recommend limiting total dietary calcium intake to 800-1,000 mg/day or less (including dietary calcium, calcium supplementation, and calcium-based phosphate binders) in adults with CKD 3-4 not taking active vitamin D analogs. Although phosphate intake to 800-1,000 mg/day (800-1,300 in KTR) was recommended previously (29,30), new guidelines suggest adjusting dietary phosphorus intake to maintain serum phosphate levels in the normal range (18). Limiting processed foods with phosphorousbased additives and encouraging home-cooked meals from fresh ingredients (preferably plant-based foods) should be the first-line interventions for phosphorus restriction (31). As in the general population, vitamin D intake for CKD patients is recommended at 600-800 IU/day, but the optimal vitamin D levels in serum remain controversial (31,32).

PRACTICE STRATEGIES: NEED FOR INDIVIDUALIZATED AND NOT TOO RESTRICTIVE DIET
Because a "kidney" diet comes with many restrictions, adherence to such a diet can be difficult and problematic (5). Too many restrictions should be avoided (18), as they can lead to poor intake. Modifications in diet are rarely required for patients with a GFR ≥60 ml/min/1.73 m 2 . Such patients should be advised to follow the same dietary recommendations as for the general population [low sodium and refined sugar, avoidance of red and processed meats, and high content of fruits, vegetables, legumes, fish, poultry, and whole grains (33)]. However, in the later stages of CKD, diet must be modified across the spectrum of the disease, according to the type of renal replacement therapy if any, and the presence of other comorbidities (5).

Biosynthesis and Degradation of Proteins
Protein digestion includes the process of breaking down proteins into their constituent AAs, which can be used either to create proteins or as an energy source, the later especially in times of starvation (34). Unlike carbohydrates and fats, if proteins are consumed in excess, the body has no capacity for their storage. As a result, excess AAs consumed are processed, being the hydrocarbon skeletons stored as fat, while the surplus of nitrogen must be removed, in as much as nitrogenous waste products are harmful, and there are no nitrogenous compounds in energy-transduction pathways (35). This is especially relevant for CKD patients, in whom consuming diets rich in protein leads to the accumulation of nitrogenous waste products and ions, causing the uremic syndrome. Transamination reactions are reversible and can thus be used to synthesize AAs from αketoacids (36,37). However, human beings cannot synthesize all of the AAs (the so-called essential AAs), which must be supplied in the diet. A deficiency of even a single AA leads to a negative nitrogen balance. In this state, more protein is degraded than is synthesized, so more nitrogen is excreted than is ingested (38). The latter is particularly relevant for CKD patients under low protein diet (LPD), who may be at risk for developing proteinenergy wasting (PEW) if not adequately monitored.

Effects of Amino Acids and Proteins on Renal Hemodynamics
Excess nutritional load of AAs dilates the "afferent" arteriole, increasing intraglomerular pressure and resulting in "glomerular hyperfiltration" and increased renal plasma flow (39). Glomerular hyperfiltration may contribute to progression of CKD (40)(41)(42)(43). Conversely, a lower protein intake leads to greater constriction of the afferent arteriole, resulting in a reduction in GFR (Figure 1). In addition to hemodynamicmediated mechanisms, protein restriction may protect against CKD progression by changes in cytokine expression and matrix synthesis (5).

Metabolic Adaptation to a Reduction in Protein Intake
Most authors agree that, in the absence of intercurrent disease, the protein requirements for patients with CKD are not substantially different from those of healthy subjects (44). In normal healthy adults, the minimum dietary protein intake to prevent negative nitrogen balance is approximately 0.6 g/kg/day. Maintaining this LPD or a very low protein diet (VLPD) of nearly 0.3 g/kg/day supplemented with AAEs and KAs are sufficient to achieve nitrogen balance and normal nutritional parameters (45,46). As in healthy subjects, CKD patients, can improve AA utilization and nitrogen balance during LPD and VLPD by activating appropriate adaptive responses (47). These include normal anabolic responses to dietary protein restriction (suppression of AA oxidation) and feeding (stimulation of protein synthesis and inhibition of protein degradation), and the recycling of AAs derived from protein breakdown (35,36). It is important to note that these diets require sufficient caloric intake to effectively use dietary protein (48).

Benefits of Protein Restriction on Kidney Outcomes
The benefits of LPDs include slowing the progression of CKD and reducing uremic symptoms and metabolic disorders (20,21,48,49). Nearly 20 RCTs have assessed the effects of protein restriction on several renal outcomes, including CKD progression, proteinuria, phosphate levels, acidemia, and BP, which have been summarized in several meta-analyses and two Cochrane reviews (8-11, 15, 16, 50-56). Overall, the balance of evidence suggests a benefit of dietary protein restriction. The 2020 KDOQI guidelines recommend, in non-diabetic adults with CKD 3-5 who are metabolically stable, protein restriction for reducing the risk of progression to end-stage renal disease (ESRD) and death (evidence 1A), and improve quality of life (1C). In adults with CKD 3-5 and who have diabetes, the guidelines suggest (with an evidence grade of "opinion") a higher protein intake up to 0.8-0.9 g/kg/day (18). For the study of the effect of LPD on survival, they identified five RCTs. Three studies clearly indicated a beneficial effect of moderate restriction in dietary protein in the development of FIGURE 1 | The effects of different nutritional interventions to slow progression of CKD. Schematic representation of reno-protective mechanisms related to protein and diet restriction. These effects can be synergistic with the mechanisms of angiotensin-converting-enzyme inhibitors and angiotensin-receptor blockers, which dilate the efferent arteriole and reduce intraglomerular pressure and glomerular damage. Adapted from Kalantar-Zadeh and Fouque (5). CKD, chronic kidney disease; GFR, glomerular filtration rate; TGF-β, transforming growth factor beta.
ESRD/renal death (57-60), whereas two studies did not (61,62). The results of the secondary analysis on the number of ESRD/renal death events combined from the three positive studies indicated a beneficial effect of protein restriction (OR 0.621; 95% CI: 0.391-0.985). For the effect of LPD on quality of life, they identified a single RCT that demonstrated how the group with protein restriction presented significantly higher scores for general health and state physical compared to the control group (62). For the study of the effect of VLPD supplemented with AAEs and KAs, they reviewed a total of 13 RCTs and one non-RCT (63-76). The pooled analysis indicated a probable overall benefit of VLCD+KAs supplementation for the development of ESRD/renal death in patients with CKD stages 3-5 (RR 0.65; 95% CI: 0.49-0.85). After the 2020 K-DOQI guidelines, a new systematic review and meta-analysis explored the effectiveness and safety of VLCD supplemented with KAs compared to LPD or a normal protein diet in patients with CKD (15). Seventeen RCTs with a total of 1,459 patients were included. KAs-supplemented VLCD significantly conserved GFR and reduced proteinuria, phosphorus and parathyroid hormone levels, systolic and diastolic BP, as well as serum cholesterol. Additionally, the analysis by subgroups showed how the VLPD supplemented with KAs was superior to the LPD with KA in the rate of decrease in GFR. Evidence for the benefits of protein restriction in KTR remains elusive (18,19). Reasons for this limited evidence include the common requirement for a LPD of being metabolically stable, a difficult condition to achieve for patients under immunosuppressive treatment. However, many of KTR have a reduced nephron mass and, therefore, could benefit from protein restriction (77). In a crossover RCT, Rosenberg et al. examined the effects of dietary protein restriction in 14 patients with Frontiers in Medicine | www.frontiersin.org chronic kidney rejection. Low protein diet was associated with a significant improvement in plasma renin activity without any change in BP, GFR, or renal plasma flow. Studies are needed to establish the efficacy and the safe level of dietary protein restriction in KTR (78).

Challenges and Risks for Protein Restriction Diets
Major concerns for LPD/VLPD are adherence and safety (79)(80)(81). Patients' adherence to these dietary regimens is low, being the knowledge and the satisfaction that the patients obtain from diet compliance the main determinants of adherence (82). Even if the patients are well-informed about the benefits of LPD/VLPD, some of them may find it difficult to adapt their lifestyles to the diet. Accordingly, it is of paramount importance to educate patients about the role of diet therapy with protein restriction for the treatment of CKD, taking into account their eating habits and preferences (81,83). Regarding nutritional security, it has been definitively demonstrated that PEW is extremely rare in patients with CKD provided that the energy intake is in the normal-high range (30-35 kcal/kg/day), the protein intake is increased in case of acute illness or hospitalization, and provided that a nutritional assessment is periodically conducted (7,18,80). Consequently, trained personnel (ideally a registered dietitian nutritionist) is strongly recommended to develop individualized dietary programs and routinely monitor and advise patients (18,80,82,84). However, this approach is time and money consuming (80). An option for those centers in which dedicated personnel (i.e., dietitian) is not available or the expertise of the nephrologist in managing diets is not optimal may be found in simplified and practical approaches to LPD (80,85,86). Indeed, even small reductions in protein intake as low as 0.2 g/kg/day may also delay the need for dialysis treatment (10,56,80). In these Nephrology Units devoid of dieticians, protein intake may be assessed by urinary urea-N excretion, whereas weight and other anthropometric methods (e.g., skinfold thickness) may be useful for indirectly monitoring caloric intake and body fat (85,87).

Effects of the Nature of Protein. Is a Vegetarian Diet an Option?
There is insufficient evidence to recommend a particular protein type (plant vs. animal) in terms of the effects on CKD progression or nutritional status (18). However, several observational studies have suggested that plant proteins may have more renoprotective effects than animal proteins. A diet rich in protein from plant sources may slow the progression of CKD (88-92), decrease proteinuria (93,94), lower the level of uremic toxins (94)(95)(96)(97)(98)(99), phosphorus intake, and the endogenous production of acid (89,90,100,101). Moreover, that such diet could potentially improve survival (102). However, the confounding factors inherent in a diet rich in plant-based protein (i.e., higher intakes of vitamins and antioxidants) make it difficult to draw definite conclusions (103,104). In a RCT, Garneata et al. compared a KA-supplemented vegetarian VLPD with conventional LPD in 207 CKD patients (89). The probability to reach the end point (i.e., KRT or a >50% eGFR reduction) was lower in the supplemented VLPD group than in the LPD group.

DIETARY SALT RESTRICTION
Dietary sodium intake is a modifiable factor that can impact on the risk of CKD progression as well as on cardiovascular disease in CKD patients. Previous reports have demonstrated the effect of sodium intake on fluid overload and hypertension, both predictors of kidney progression and cardiovascular remodeling (105)(106)(107)(108)(109). In addition, high sodium intake might have direct toxic effects on blood vessels (109,110). High salt intake is also a well-established risk factor for hypertension in KTR and can result in decreased graft survival (2,111).
Conversely, salt restriction RCTs demonstrate a reduction in BP and proteinuria, with potential benefits on CKD progression and survival (5). A Cochrane review summarized the effects of salt restriction in CKD (8). Unfortunately, these studies did not show collectively a beneficial effect of a lower sodium intake on mortality, cardiovascular events, or CKD progression, probably due to their short follow-up and the limited sample size. It is interesting to highlight a significant decrease in proteinuria associated to a low salt diet, that was observed in all the RCTs that reported this outcome (112)(113)(114)(115). The 2020 KDOQI guidelines recommend in adults with CKD 3-5 (1B), CKD 5D (1C), or postransplantation (1C), a limitation in the sodium intake to <2.3 g/d (<100 mmol/d) to achieve a BP reduction, an improvement in volume control and a decrease in proteinuria levels (2A) (18). Nevertheless, the lack of longterm RCTs assessing the effectiveness and safety of dietary salt restriction on CKD progression and survival prevents any firm conclusions about these hard outcomes.

DIETARY CALORIC RESTRICTION
Obesity constitutes a risk factor for diabetic and non-diabetic kidney disease (128), and there is some evidence suggesting that weight reduction through diet and lifestyle modifications could be considered as a component of the reno-protective regimen of obese patients with ND-CKD (129). Bariatric surgery reduces risk factors implicated in the progression of kidney injury in obesity and type 2 diabetes mellitus (130,131). Dietary calorie restriction and exercise may reduce oxidative stress and inflammatory in patients with moderate to severe CKD (132), whereas weight loss may lead to better BP control and reduction of the obesity-related glomerular hyperfiltration and proteinuria (133)(134)(135)(136).

FIBER INTAKE AND PROBIOTICS
Evidence is emerging for the effects of fiber intake on uremic toxins generation (104,137,138). In a placebocontrolled RCT involving 30 patients with ND-CKD, total plasma p-cresol concentration was reduced by 40% after taking a synbiotic for 4 weeks (139). According to a recent meta-analysis involving eight studies of 261 patients with CKD stages 3-5D, probiotics supplementation may reduce the levels of p-cresol sulfate and elevate the levels of IL-6, thereby protecting the intestinal epithelial barrier of patients with CKD (14). However, it remains uncertain if increasing fiber intake to normalize intestinal microflora could delay CKD progression.

DIETARY PATTERNS AND CKD PROGRESSION
Historically, research recommendations and guidelines have focused primarily on modifying the single intake of micro or macronutrients (57). However, eating habits generally remain little over time for each individual, so that the overall dietary pattern may be more decisive for patients than an excess or deficiency in one specific nutrient (103). Adherence to healthy diet patterns as the Mediterranean and the DASH (The Dietary Approach to Stop Hypertension) diets has been linked to less rapid kidney function decline and favorable effects on cardiovascular morbidity and mortality in ND-CKD patients, including KTR (140,141). Plant-based diets could also mitigate metabolic acidosis in patients with CKD and potentially slow the progression of kidney disease, but evidence is limited (104). Conversely, a Western diet (rich in saturated fat, red and processed meat, and sweets) has been associated with an increased risk of CKD progression and albuminuria (142). The evidence is not conclusive as not all studies associate healthy dietary patterns and risk of ESRD (143). Evidence from interventional studies is also very limited (144,145). Altogether, there is a possibility that healthy dietary patterns may prevent the development of ESRD (5,81,146).

CONCLUSIONS
Close monitoring to adherence to dietary recommendations and frequent evaluation of nutritional status is fundamental in the management of patients with CKD, since it can affect important health outcomes, including CKD progression, quality of life, morbidity, and mortality. Within these nutritional measures, salt restriction, LPD and VLPD supplemented with AAs and KAs of nitrogen-free AAs, have been shown in recent metaanalyzes of RCTs to be effective in modifying the natural history of CKD, delaying the fall of the GFR, decreasing proteinuria, BP levels, or bone mineral disorder parameters, without increasing the risk of PEW. Patients' preferences and compliance have to be considered when prescribing LPD/VLPD in order to increase the adherence. Additional nutritional measures to delay CKD progression, some of them considered as experimental, may include the limitation of phosphate and calorie intake, the increase of fiber intake, and the promotion of healthy dietary patterns.

AUTHOR CONTRIBUTIONS
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.