Personalized nutritional management in the transition from non-dialysis dependent chronic kidney disease to dialysis

Impact on delaying dialysis initiation and/or survival

High dietary protein intake may contribute to progressive decline in kidney function through the dilation of afferent arterioles, aggravated glomerular hyperfiltration and intraglomerular hypertension, and upregulation of proinflammatory gene expression [10,11]. Thus, clinical practice guidelines recommend the utilization of LPDs to reduce the risk of ESKD and/or mortality in the nutritional management of moderate-to-advanced NDD-CKD patients [12,13]. The recently updated 2020 National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guidelines for nutrition in CKD recommend that adults with stages 3 to 5 NDD-CKD without diabetes who are metabolically stable should consume 1) an LPD of 0.55 to 0.60 g/kg body weight/day, or 2) a very low protein diet (VLPD) of 0.28 to 0.43 g/kg of body weight/day with additional ketoacid analogs in order to reduce the risk of ESKD and/or death and to improve HRQOL. The KDOQI guidelines also indicate that it is reasonable to prescribe a lower dietary protein intake of 0.6 to 0.8 g/kg/day among adults with stages 3 to 5 NDD-CKD and underlying diabetes. These recommendations have been endorsed by the International Society of Renal Nutrition and Metabolism, which has advised that it is also reasonable for clinicians to aim for the lower end of a streamlined target of 0.6 to 0.8 g/kg/day irrespective of the etiology of CKD, considering that lower dietary protein targets may be challenging to achieve without compromising energy intake or in settings without access to ketoacid supplements. Furthermore, among the clinical trials of LPDs, the actual amount of protein consumed was typically above 0.6 g/kg/day despite a prescribed target of 0.55 to 0.6 g/kg/day.

The kidney protective effect of dietary protein restriction has been demonstrated as far back as the 1960s, including a study of eight patients with chronic uremic symptoms among whom an LPD led to a reduction in nitrogen waste products and uremic symptoms [14]. Subsequent research has shown that LPDs reduce the progression of kidney disease by reducing the compensatory hemodynamic changes and glomerular hyperfiltration of CKD [15]. In addition to reducing glomerular hyperfiltration, intraglomerular hypertension, and cellular injury [11], LPDs and/or supplemented VLPDs may reduce mesangial proliferation, glomerulosclerosis, and kidney fibrosis vis-à-vis amelioration of kidney inflammation and oxidative stress [16]. Despite strong evidence supporting the benefits of LPDs on CKD outcomes, the efficacy and safety of this dietary intervention still remains widely debated. The main findings of the MDRD (Modification of Diet in Renal Disease) study concluded that there was no effect of an LPD (i.e., 0.58 g/kg/day) on reducing CKD progression and that a VLPD had a slightly but not clearly significant effect on reducing the decline in GFR levels vs. higher dietary protein intake (i.e., 1.3 g/kg/day). However, expert opinion/commentaries have indicated that these findings are not definitive [17] due to 1) the study cohort composition not being generalizable to the broader CKD population (i.e., under-representation of patients with diabetes and over-representation of patients with polycystic kidney disease), and 2) secondary analyses of the data examining GFR trajectories after 3 months showing significant reduction in CKD progression in the low-protein diet arm [18]. Other studies have demonstrated that LPDs slow the decline in GFR and delay requirements for renal replacement therapy in CKD patients with [19] and without diabetes [20]. For example, a meta-analysis of 16 randomized controlled trials of LPDs in NDD-CKD demonstrated that dietary protein restriction was associated with lower risk of ESKD, greater survival, higher serum bicarbonate levels, lower serum phosphorus levels, and less azotemia [21]. Another randomized controlled trial has shown that a ketoacid analog supplemented with VLPD (dietary protein intake of 0.3 g/kg/day) mitigated kidney function decline and reduced the number of patients requiring renal replacement therapy [22]. Emerging data also demonstrate the benefits of LPDs in kidney disease patients of older age, who comprise a large proportion of the CKD population [9]. Indeed, a growing body of literature has shown that LPDs have kidney protective effects in both older and younger patients with CKD [23]. In a recent study of 352 patients with stages 3 to 5 NDD-CKD from Japan who were stratified by age, after a median follow-up of 4.2 years, it was found that moderate dietary protein intake (i.e., >0.8 g/kg/day) was associated with faster decline in eGFR among the overall cohort and in those of elder age (>65 years) as compared with low protein intake (i.e., 0.6–0.8 g/kg/day) and very low protein intake (i.e., <0.6 g/kg/day) [24]. In another study of 56 NDD-CKD patients from Italy that specifically examined the impact of LPDs in the elderly population (>70 years of age), a ketoacid analog supplemented very low protein vegan diet was shown to delay dialysis transition by approximately 1 year vs. non-restriction of dietary protein intake [25].

Impact on incident chronic kidney disease and/or chronic kidney disease progression

In addition to the amount of dietary protein intake, the source of dietary protein (animal vs. plant-derived) may have an important bearing on CKD-related outcomes, including the incidence and/or progression of CKD, risk factors for developing CKD, and CKD-related complications. While there are a variety of plant-based diets (e.g., Mediterranean, dietary approaches to stop hypertension, flexitarian, vegetarian, and vegan diets), which are defined as eating patterns with a large proportion of plant-dominant foods, it is important to underscore that not all plant-based diets are per se LPDs. Hence, there are ongoing studies that are examining the efficacy of a plant-dominant LPD (PLADO), which is comprised of a lower dietary protein intake of 0.6 to 0.8 g/kg/day originating from >50% plant-based sources, that is also high in fiber (>25 g/day), low in sodium (<4 g/day), and with adequate caloric content (30–35 kcal/kg/day) [26], including a National Institutes of Health-funded clinical trial of the PLADO in patients with diabetic kidney disease (PLAFOND [Plant-Focused Nutrition in Patients With Diabetes and Chronic Kidney Disease] trial) [27]. To optimize the effectiveness, safety, and adherence of these dietary interventions, collaboration with specialty-trained kidney dietitians in administering the PLADO/PLAFOND diet and medical nutrition therapy is of paramount importance.

A growing number of studies have shown that plant-based diets may favorably impact kidney disease endpoints, including lowering of glomerular hyperfiltration [28], amelioration of incident CKD and/or CKD progression [29–31], and reduction of mortality risk [32]. For example, in a study of 11,952 participants from the ARIC (Atherosclerosis Risk in Communities) cohort who had normal underlying kidney function and underwent food frequency questionnaires, after a median follow-up of 23 years both red meat and processed meat consumption were associated with higher risk of developing CKD. In contrast, a higher dietary intake of nuts, legumes, and low-fat dairy was associated with a lower risk of incident CKD. In another study of 1,624 female participants from the Nurses’ Health Study (including 1,135 and 489 participants with and without CKD, respectively), higher vegetable protein intake was associated with a lower risk of GFR decline compared to higher nondairy protein intake. Clinical trials examining the effects of plant-based diets on kidney disease markers are sparse but have shown promising outcomes. In a randomized controlled trial 41 patients with type 2 diabetes and CKD who were randomized to a soy protein (comprised of two-thirds soy/vegetable protein) vs. control diet (comprised of two-thirds animal protein), after a follow-up period of 4 years those in the soy protein group had significantly lower glucose, lipid, and inflammatory markers (i.e., C-reactive protein), as well as proteinuria [33]. In another clinical trial of 207 patients with stages 4 to 5 CKD without diabetes who were randomized to a supplemented vegetarian VLPD vs. a conventional LPD, those in the vegetarian LPD arm were less likely to experience the primary composite endpoint of renal replacement initiation and/or >50% reduction in eGFR (13%) vs. those in the LPD arm (42%).

Impact on chronic kidney disease-related complications

PLADOs may also favorably impact various CKD-related complications, including mineral bone disease, metabolic acidosis, uremic toxin generation, and mortality risk. The higher contents of nonadditive derived dietary potassium, nonadditive derived dietary phosphorus with lesser bioavailability, and dietary fiber in plant-derived foods (i.e., vegetables, fruits, legumes, nuts, and whole grains) might partly explain the favorable effects of plant-based proteins on kidney health. First, plant-based LPDs reduce dietary phosphorus load and hyperphosphatemia, resulting in a decrease of fibroblast growth factor 23 (FGF23) levels [34] as a risk factor for cardiovascular morbidity (i.e., left ventricular hypertrophy, cardiovascular events), death, and dialysis initiation [35,36]. In a crossover trial of nine CKD patients who underwent 1 week of a meat diet and 1 week of a vegetarian diet, during the vegetarian diet period patients demonstrated lower serum phosphorus levels, which resulted in a reduction of serum parathyroid hormone and FGF23 levels [37]. Second, whereas animal-based proteins and foods generate acid due to being comprised of sulfur-containing amino acids (i.e., methionine, cysteine) and cationic amino acids (i.e., lysine, arginine), plant-based proteins are base producing due to the presence of natural dietary alkali (i.e., citrate, malate) that are converted to bicarbonate [38–40]. Hence, plant-based LPDs mitigate net acid generation, and two clinical trials in NDD-CKD patients have shown that increased fruit and vegetable intake had greater efficacy in improving acidemia than sodium bicarbonate therapy and/or usual care [41,42]. Third, PLADOs may modulate the gut microbiome’s generation of various uremic toxins including trimethylamine N-oxide (TMAO), p-cresol sulfate, and indoxyl sulfate, which may relate to greater dietary fiber content [43]. In an experimental animal model of CKD, administration of fiber led to decreased production of p-cresol sulfate, increased production of short-chain fatty acids (i.e., which may have favorable effects on systemic hypertension, glucose and lipid metabolism, and cardiovascular health [44]), and kidney injury [45]. In a clinical study of 26 patients without CKD among whom 15 patients consumed a vegetarian diet whereas 11 patients consumed an unrestricted diet, vegetarians had lower production of both p-cresol sulfate and indoxyl sulfate, and it was found that the lower excretion of p-cresol sulfate and indoxyl sulfate among vegetarians was linked with greater fiber intake and lower protein intake [46]. In a clinical trial of 56 hemodialysis patients who were randomized to supplements with vs. without increased dietary fiber, those in the dietary fiber arm experienced a greater reduction in indoxyl sulfate and p-cresol sulfate vs. those in the control arm [47]. Other salutary effects of greater dietary fiber intake include improvements in blood pressure control, glycemic status, lipid levels, and gastrointestinal motility/constipation symptoms [48]. Finally, observational data suggest that greater plant-based and lesser animal-based protein consumption may favorably impact survival. In an observational study of 1994 participants with eGFRs of <60 mL/min/1.73 m² from the National Health and Nutrition Examination Survey, increasingly higher intake of protein from high biological value protein sources (which have an amino acid composition similar to human protein and are typically from animal sources) was associated with incrementally higher all-cause mortality risk [49].

Dietary potassium intake considerations

Although restriction of dietary potassium intake has been a longstanding paradigm in the nutritional management of advanced CKD patients given concerns about hyperkalemia and its complications (i.e., cardiac arrhythmias, accelerated initiation of renal replacement therapy), the efficacy and safety of this approach has not been informed by rigorous evidence. Furthermore, there is growing recognition that imposing excessive dietary potassium restriction may inadvertently lead to a missed opportunity among CKD patients to encourage greater consumption of plant-based heart-healthy foods which tend to be from potassium-rich sources [50]. Indeed, observational studies from participants with and without kidney dysfunction have revealed that lower dietary potassium intake is associated with higher mortality risk [51,52]. There are various plausible mechanisms by which higher dietary potassium intake may favorably impact kidney and cardiac health. First, a diet high in potassium can lower blood pressure and improve or protect kidney and/or cardiac function by reducing vascular resistance [53,54]. Second, high potassium intake may promote vasodilation and reduce the risk of glomerulosclerotic lesions and tubular injury by increasing renal kallikrein expression [55,56]. Third, increased endothelium-dependent nitric oxide production and decreased salt-induced transforming growth factor beta production induced by higher potassium intake may promote vascular protection against atherosclerosis, thereby further preventing kidney and cardiovascular complications [57]. Fourth, dietary patterns that are rich in potassium are generally comprised of healthy fruits and vegetables [58,59], which may further engender lowering of blood pressure and blunting the progression of renal dysfunction via antioxidant and anti-inflammatory effects [60]. Hence, concurrent use of potassium binders paired with PLADOs may reduce the risk of hyperkalemia while allowing patients to relax the dietary restrictions with respect to greater plant-based food intake [61,62]. Future studies are necessary to determine the long-term efficacy and safety of a plant-based potassium-liberalized diet paired with a potassium binder vs. a potassium-restricted diet.