*2.2. Very Low-Protein Diet*

Low-protein diets and very low-protein diets (VLPD) (0.28–0.43 g/kg/body wt/d) may be achieved with nutrition supplementation with essential amino acids (EAAs) and ketoanalogues [27] to safeguard against PEW. The KDOQI guidelines recommend restricting protein to slow ESRD progression and improve quality of life (QoL) by reducing symptoms for metabolically stable patients [18]. The NKF defines metabolically stable as being absent from inflammatory or infectious diseases, poorly controlled diabetes, consumptive diseases, antibiotics or immunosuppressive medications, significant short-term loss of body weight, and no hospitalizations within two weeks [18,29]. For patients with CKD stage 3–5, a protein restriction providing 0.55–0.60 g/kg/body wt/d or a VLPD with supplementation with ketoacid analogues is recommended [18,29]. Diabetic adults with CKD 3–5 are recommended a protein diet providing 0.6–0.8 g/kg/body weight/d, and patients on maintenance hemodialysis (HD) or peritoneal dialysis (PD) with or without diabetes are recommended a protein intake providing 1.0–1.2 g/kg/body weight/d [20,30]. Diet modifications, such as reducing protein from heme sources and including plantbased proteins, protect against metabolic acidosis by lowering acid production; these effects are mostly seen with a VLPD (0.3–0.5 g/kg/body weight/d) with supplementation with ketoacid analogues [27,29]. Conservative reductions in protein intake as small as 0.1–0.2 g/kg/day have shown significant effects in preserving kidney function, hence slowing CKD progression [31]. A randomly controlled trial (RTC) reported a vegetarian (VLPD) (0.3 g/kg/body wt/d) supplemented with ketoanalogues compared with a standard LPD (0.6 g/kg/body wt/d) ameliorated kidney function decline over time and reduced the need for renal replacement therapy (RRT) [32].

An alternate protein source may be more beneficial to the patient's health than restricting the amount of protein alone; the protein source may be of greater importance than the quantity [18,29]. Plant proteins are typically ingested along with fiber, phytonutrients, and antioxidants, although animal proteins are ingested along with saturated fat and cholesterol [2]; this may be one reason plant proteins are associated with a more vast decline in blood pressure compared to animal protein, as shown from the INTERMAP Study on micronutrients and macronutrients on blood pressure [33]. Additionally, animal protein is associated with decreased insulin sensitivity, increased reactive oxygen species (ROS) [34], and induced hyperfiltration [35]; ingesting an equal amount of plant protein does not promote the same effects [36]. Most of the food within plant-based diets come from plant sources [37,38]. These types of diets are generally lower in protein and saturated fat, contain higher levels of potassium and phosphorus, are richer in fiber, and provide the body with additional nutrients in the form of vitamins, minerals, and phytochemicals. Adopting a plant-based diet has been shown to have numerous health benefits, such as a reduction in atherosclerotic plaque buildup, decreased risk of cardiovascular disease, decreased BMI, reduced body weight, and lower blood pressure [39,40], which are parameters that are clinically relevant for management of CKD patients [39].

Reductions in daily protein have produced some evidence in slowing CKD progression [41] by retarding the rate of kidney function decline [42]. However, determining an optimal amount of protein for CKD is complicated, especially when assessing the patient's individual circumstances [43]. When considering a protein-restricted diet, the patient's individual nutritional status should be evaluated with caution [41]. All previous protein-restricted diet studies are inconclusive [23,44].

#### *2.3. Vitamin D*

The primary role of vitamin D (VD) is to activate intestinal calcium reabsorption [45], but as kidney disease progresses, alterations in the biological mechanism occur. Low levels of active VD in ESRD patients are associated with increased bone reabsorption and reduced bone mineral density [46]. Studies report a progressive decline in VD of more than 80% from CKD 1–5, dialysis [47], and transplant patients [48]. Vitamin D metabolism is interrupted by the inability for the second hydroxylation step of 25-hydroxyvitamin D

to occur, which converts it to the active form 1,25 dihydroxy vitamin D, which occurs in the kidneys [49]. Inhibition of 1,25 dihydroxy vitamin D induces hypocalcemia, which stimulates the parathyroid gland to release parathyroid hormone at persistent circulating levels [50,51]. Over time, this may result in renal osteodystrophy, including secondary parathyroidism, osteitis fibrosa, osteomalacia, and adynamic bone disease [45].

The current KDOQI guidelines for CKD nutrition state ergocalciferol or cholecalciferol effectively treats VD deficiency/inefficiency; however, specific dosing should be individualized and derived through a step-by-step approach [17]. This step-by-step approach includes monitoring 25(OH)D serum levels and serum calcium and serum phosphorus, which helps the healthcare team recommend specific dosing veered to the patient's individual requirements [18]. Supplementation with ergocalciferol or cholecalciferol is essential in treating and preventing BMD disease in CKD [50,51]. A meta-analysis performed by Kandula et al. [52] suggests that supplementation of 1,25 dihydroxy vitamin D in CKD leads to increase in the serum levels and improves biochemical end-points. The study failed to observe any clinically significant outcomes due to observed improvements in biochemical end-points [52].

#### *2.4. Calcium*

Calcium balance is regulated by intestinal calcium absorption, kidney reabsorption, and calciotropic hormones that activate calcium exchange from the bone when serum calcium levels are low [18]. Insufficient calcium absorption and chronic calcium deficiency result in increased risk for hyperthyroidism and osteitis [17]. However, excessive calcium poses an increased risk for calcification, resulting in comorbidities and higher mortality [17]. Alterations in calcium metabolism are multifactorial and include the use of active vitamin D analogues. Research shows that ingesting about 800–1000 mg/d of calcium may be sufficient to maintain calcium balance for patients with CKD 3–4 in the absence of vitamin D analogues [17] (Table 2). However, calcium recommendations for early stages of CKD typically follow the RDA (1000–1200 mg/d) for adults because the level of kidney function has not yet disrupted calcium balance, although this is in individualized circumstances. Maintaining calcium balance is more complicated for CKD patients on dialysis, and hypercalcemia is relatively standard. Vitamin D is an important factor in maintaining calcium balance. VD supplementation therapy is prescribed to CKD patients with inefficient active VD levels to increase calcium reabsorption and prevent high serum para-thyroid hormone (PTH) and bone turnover [53]. Massart et al. [54] and Jean et al. [53] reported increased 1,25(OH)2D levels after cholecalciferol supplementation. Strong evidence shows the importance of adequate active VD for calcium balance, and it is achieved with VD supplementation in CKD patients [18].
