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 (1–3). 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 (5–7).

In recent years, several studies, trials, and meta-analyses have evidenced the effectiveness of protein restriction and others nutritional interventions on kidney outcomes (8–17). 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.

Table 1 shows current recommendations for nutritional requirements in adult patients with non-dialysis CKD (ND-CKD), and kidney transplant recipients (KTR) (18, 19). A caloric intake of 25–35 kcal/kg/day is recommended to counteract the excess resting energy expenditure secondary to inflammation and comorbidities, as well as for preserving a neutral or positive nitrogen balance. However, this recommendation should be individualized according to the patient's profile, including age, lean body mass (which is the primary determinant of energy expenditure), physical activity, and the underlying etiology of kidney disease (20, 21). According to the 2020 KDOQI guidelines, the recommended protein intake for stable patients with ND-CKD 3–5 dialysis is 0.55–0.60 g/kg/day, which can be reduced to 0.28–0.43 g/kg/day if it is supplemented with 7–15 g/day of KAs and essential AAs. In the case of diabetic patients, guidelines suggest a higher protein intake up to 0.6–0.8 g/kg/day to glycemic control. Any intercurrent catabolic episode may require increasing energy and protein intake independently of CKD stage (22). Regarding protein quality, there is no consensus on whether the protein source impacts differently on the risk of CKD progression (18).

Kidney transplant recipients requires a different nutritional management depending on the post transplantation period. During the perioperative period, KTR need to adequate their intake of energy to 35–40 kcal/kg/day and of proteins up to 1.4 g/kg/day for at least 4 weeks (19) to compensate the increase in protein catabolism subsequent to the use of steroid and surgical stress. However, in the maintenance phase, the goal is to optimize the nutritional status with a slight reduction of the caloric intake down to 30 kcal/kg/day. Obese KTR should reduce their caloric consumption to levels lower than their energy expenditure, being values close to 25 kcal/kg/day an adequate approximation (19). Due to the lack of available studies in this population (23), it has been proposed that those with normal kidney function should follow similar recommendations to the general population, whereas for KTR with chronic allograft dysfunction, it is recommended to provide a protein-restricted diet just as in ND-CKD (19).

A modest sodium restriction (<2.3 g/day) is recommended for the management of CKD patients to achieve better volume control, reducing BP, and proteinuria synergistically with available pharmacologic interventions (18). A daily fiber intake of 25–30 g/day or more for CKD patients may be suggested, being this amount similar to recommendations for the general population (7). Potassium restriction in CKD may prevent from complying with this recommendation but in general terms CKD patients do not require aggressive dietary potassium restriction until advanced stages or if hyperkalemia risk is judged high (24–26). Recently, it has been suggested to avoid high potassium foods with poor nutritional value (i.e., bran products, or salt substitutes) and correct other causes of hyperkalemia, such as metabolic acidosis or use of renin-angiotensin-aldosterone system (RAAS) inhibitors, before restricting healthy foods (27). Acidosis is a key risk factor in the progression of CKD, 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 phosphorous-based 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).

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 m². 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).

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 (105–109). 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 (112–115). 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 long-term RCTs assessing the effectiveness and safety of dietary salt restriction on CKD progression and survival prevents any firm conclusions about these hard outcomes.

Phosphate-specific diet therapy provided by a dietitian may reduce phosphate levels in CKD, although overall certainty of evidence is low (116). However, association between hyperphosphatemia and adverse cardiovascular outcomes and CKD progression is robust in this population (117–124), also in KTR (125–127). Altogether, it seems reasonable to recommend adjusting dietary phosphorus intake to maintain serum phosphate levels in the normal range (18, 105).

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 (133–136).

Evidence is emerging for the effects of fiber intake on uremic toxins generation (104, 137, 138). In a placebo-controlled 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.

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).

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 meta-analyzes 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.

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

PM acknowledges consultation or speaker fees from Abbott Nutrition, Amgen, Baxter, Fresenius-Kabi, Nutricia, Palex, Sanofi-Genzyme, and ViforPharma. JC acknowledges speaker fees from Abbott Nutrition, Baxter, Fresenius, and Nutricia. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.