Dietary Interventions in Autosomal Dominant Polycystic Kidney Disease

ABSTRACT

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive growth of renal cysts, leading to the loss of functional nephrons. Recommendations for individuals with ADPKD to maintain a healthy diet and lifestyle are largely similar to those for the general population. However, recent evidence from preclinical models suggests that more tightly specified dietary regimens, including caloric restriction, intermittent fasting, and ketogenic diets, hold promise to slow disease progression, and the results of ongoing human clinical trials are eagerly awaited. These dietary interventions directly influence nutrient signaling and substrate availability in the cystic kidney, while also conferring systemic metabolic benefits. The present review focuses on the importance of local and systemic metabolism in ADPKD and summarizes current evidence for dietary interventions to slow disease progression and improve quality of life.

Statement of Significance: We offer the first comprehensive review of the current evidence for dietary interventions to slow ADPKD progression from preclinical animal models and early-stage clinical trials, and elucidate potential common mechanisms underlying their effect.

Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease. It is characterized by growth of cysts originating in the epithelia of a small proportion of nephrons (1). Over time, cyst growth damages healthy tissue and results in the progressive loss of kidney function, often culminating in end-stage renal disease (2). Disease presentation and progression are highly variable among individuals with ADPKD. Although associations between genotype and disease outcomes are clear, there is still variability in disease severity among individuals sharing the same mutation, and environmental factors amenable to lifestyle modification can meaningfully impact disease progression (1).

The worldwide prevalence of obesity has risen rapidly in recent decades, as have rates of associated metabolic diseases (3). Recently, obesity was found to be associated with a greater rate of kidney enlargement and functional decline in early-stage ADPKD (4). Components of the metabolic syndrome, including hypertension and impaired glucose tolerance, are also associated with more severe ADPKD (5). In addition to accelerating disease progression, obesity may independently increase the kidney pain experienced by those affected by ADPKD, potentially through increased mechanical stress and chronic inflammation. Patients with ADPKD most frequently report pain in the low back (6), and post hoc analysis of the Halt Progression of Polycystic Kidney Disease (HALT-PKD) trials revealed higher BMI is associated with more frequent back pain, independently of height-adjusted kidney and liver volumes (7). As the prevalence of obesity and metabolic disease continues to rise, interventions to slow disease progression and improve quality of life in patients with ADPKD and comorbid obesity are crucially needed.

General guidelines for lifestyle modifications in ADPKD do not currently include recommendations for a particular diet (8). At the same time, a growing body of evidence highlights the role of metabolic alterations in fueling cyst growth. The changes in nutrient signaling pathways and basic metabolism that occur in ADPKD are responsive to the systemic metabolic state, which is determined over time in large part by diet. Importantly, studies in preclinical animal models have shown highly promising effects of slowing disease progression through dietary interventions, including caloric restriction (CR), time-restricted feeding (TRF), and a ketogenic diet (KD). Human data support the existence of metabolic reprogramming in the cystic kidney and overall metabolic health as a modifier of the rate of disease progression, and a number of early-stage clinical trials of dietary interventions in ADPKD are in progress. If proven effective, specific diets may soon become key tools in ADPKD management. Here, we describe possible mechanisms of action and review the current evidence supporting their use.

Metabolic Reprogramming in ADPKD

The kidney has exceptionally high metabolic demands, particularly in the proximal tubule. It is second only to the heart in mitochondrial number (9), and relies heavily on fatty acid oxidation (FAO) for efficient ATP production (10). Alteration of cellular metabolism in cyst-lining epithelial cells is becoming recognized as an important pathophysiologic feature of ADPKD (11–14). Several metabolic abnormalities have been described, notably dependence on aerobic glycolysis and defective FAO. Together, these promote cyst growth at the detriment of healthy tissue function. Understanding these metabolic abnormalities is key to discerning and targeting the intersection of energy metabolism and ADPKD.

Aerobic glycolysis and glucose dependence

The reliance on glycolysis rather than oxidative phosphorylation (OXPHOS) in aerobic conditions, or the Warburg effect, was first described in cancer (15). This change in fuel source preference occurs in highly proliferative cells to support biosynthesis from glycolytic intermediates (16). In the context of ADPKD, aerobic glycolysis was first demonstrated by Rowe et al. (17) who showed increased glucose uptake and conversion to lactate in polycystin-1 (Pkd1) knockout mouse embryonic fibroblasts (MEFs) and in the cystic kidneys of Pkd1 knockout mice using ¹³C isotope tracing. Upregulation of genes encoding glycolytic enzymes was also observed in the renal cysts of patients with PKD1 mutations (Figure 1, arrow 1). Other studies have corroborated these results. Lactate concentrations were elevated in the cyst fluid of ADPKD patients at the time of transplant (18) (Figure 1, arrow 2). In an orthologous (Pkd1^+/-) mini-pig model, expression of glycolytic enzymes [hexokinase (HK) 1, phosphofructokinase 1 (PFK1), pyruvate kinase isoform M2 (PKM2)] was increased, and the activity of electron transport complexes was decreased (19). Moreover, truncation ofPkd2in HEK-293 cells altered mitochondrial morphology and resulted in more rapid acidification of the extracellular medium, suggesting that this mutation resulted in aerobic glycolysis (20). However, 2 independent reports found no increase in glycolysis in Pkd1-deficient kidney tissues or cells (21, 22). Even so, they reported reduced OXPHOS and FAO (21) or upregulation of HK2 (22), results that are consistent with a metabolic shift towards greater reliance on glycolysis (12).

FIGURE 1.

Altered cellular metabolism in ADPKD. Cyst-lining cells exhibit the Warburg effect; aerobic glycolysis is increased (red arrow 1), resulting in the extracellular accumulation of lactate (red arrow 2). In addition to glucose, highly proliferative cells have increased demands for glutamine, reflected by upregulation of GLS (red arrow 3). At the same time, fatty acid oxidation (red arrow 4) and oxidative phosphorylation (red arrow 5) are impaired. ADPKD, autosomal dominant polycystic kidney disease; GLS, glutaminase; GLUD, glutamate dehydrogenase; TCA cycle, tricarboxylic acid cycle; αKG, alpha-ketoglutarate.

The strongest evidence for glucose reliance in Pkd-deficient renal cells comes from experiments using 2-deoxyglucose (2DG). This molecule competitively inhibits the phosphorylation of glucose to glucose-6-phosphate (G6P), thereby inhibiting glycolysis (23). Two days of postnatal treatment with 2DG reduced the weight of kidneys, but not other organs, and lowered the cystic index in 2 orthologous models, one of which was slowly progressive (17). Increased uptake of ¹³C-glucose and production of ¹³C-lactate were confirmed in an orthologous and slowly progressive inducible Pkd1 knockout; 2DG treatment for 2 mo reduced kidney volume, leukocyte infiltration, and cystic index (24). Similar improvements in kidney volume and cystic index were reported with 2DG treatment in non-orthologous Han:SPRD-Cy rats (25) and mice with conditional loss of Pkd1 or Pkd2 (26). In a mini-pig model with inducible Pkd1 knockout, 2DG effectively slowed disease, and synergistic effects were observed when 2DG was combined with metformin (27). Co-treatment with low-dose 2DG with metformin in vitro also synergistically inhibited proliferation in cyst-lining epithelia from ADPKD patients (28). An ongoing phase I clinical trial aims to assess the safety and tolerability of 3-mo 2DG treatment in 18 patients with ADPKD (29).

Glutamine dependence

In addition to a greater reliance on glycolysis, proliferating cells have higher glutamine demands to support the increased biosynthesis of amino acids, nucleic acids, and glutathione (16, 30). Glutamine dependence (Figure 1, arrow 3) has been demonstrated in Pkd1-deficient kidneys. Glutamine restriction slowed cystogenesis in explants, and the glutaminase (GLS) inhibitor slowed cyst growth in Pkhd1-Cre;Pkd1^fl/fl mice (31, 32), but not in the more aggressive Aqp2-Cre;Pkd1^fl/fl model (32). Although glutamine needs were found not to differ between wild-type (WT) and Pkd1^del2/del2 MEFs (22), the GLS1-GAC isoform of GLS is upregulated in cyst-lining epithelia of human ADPKD (32). Thus, glutamine dependence is observed in some but not all animal models of ADPKD, and there is some evidence that GLS is upregulated in human ADPKD.

Certain cancers, including glioblastoma and breast cancer, rely on glutamine as a fermentable fuel. Pharmacologic strategies to deplete glutamine have been used in conjunction with limiting dietary glucose intake (KD) in this setting (33, 34). This treatment reduces glycolytic and pentose phosphate pathway flux, both of which are also aberrantly upregulated in ADPKD (13), while at the same time providing ketones as a nonfermentable fuel source for cells with intact mitochondrial OXPHOS (33). Similar to cancer cells, changes in substrate dependence in cyst-lining epithelia may render them susceptible to reduced glutamine and glucose availability (discussed in Ketosis—potential mechanisms).

Defective FAO

A second hallmark of metabolic dysregulation in ADPKD is defective FAO. A lost capacity for mitochondrial B-oxidation, the preferred energy source of the kidney, is a critical step in the pathogenesis of multiple kidney diseases (35). Impaired FAO was inferred from high concentrations of urinary acetylcarnitine in early-onset Pkd1 deletion mice, and OXPHOS was significantly downregulated (36) (Figure 1, arrows 4 and 5). This same study identified transcription factor hepatocyte nuclear factor 4ɑ (HNF-4α), an important regulator of FAO, as a transcriptional network node in ADPKD, and double knockout of Pkd1 and Hnf4a worsened cystic phenotype. Defective FAO in the renal epithelia of Pkd1 knockout mice was later confirmed, a metabolic shift which may preserve lipids for growing cysts (21).

Renal cysts occur in inherited disorders of FAO, further implicating defective FAO in the pathogenesis of ADPKD. These disorders include carnitine palmitoyl transferase (CPT) 2 deficiency (37) and multiple acyl-CoA dehydrogenase deficiency (MADD) (38–40). The prenatal manifestations of these congenital FAO enzyme deficiencies are very similar to polycystic kidney disease (41). Moreover, impaired FAO and peroxisome proliferator-activated receptor γ coactivator 1ɑ (Pgc1α) downregulation have been identified as signatures of renal tubule fibrosis (10, 42), while increased FAO in the tubular epithelia (through overexpression of CPT1A) was protective in 3 fibrosis models (43). Thus, the defective FAO observed in ADPKD may contribute to cystogenesis and fibrosis.

The downregulation of transcription factor peroxisome proliferator activated receptor ɑ (PPARα) is likely to be involved in ADPKD-associated FAO defects [reviewed in (44)]. PPARα downregulation is observed in human cysts (45) and rodent models (46, 47), potentially due to post-transcriptional inhibition by the microRNAs miR-17∼92 and miR-21 (46, 48). Treatment with PPARα agonist fenofibrate improved disease phenotype in both aggressive (46) and slowly progressing ADPKD mice (47), and ameliorated tubulointerstitial fibrosis associated with reduced FAO (10). Importantly, age-associated fibrosis in rats was slowed by CR (49), as circulating nonesterified fatty acids are endogenous PPARα ligands (50). Taken together, the above studies suggest that defects in FAO may contribute to progressive cytogenesis and kidney fibrosis in ADPKD.

Nutrient and inflammatory signaling

Changes in the metabolism of cyst-lining cells are intertwined with aberrant nutrient sensing pathway activity, notably decreases in AMP-activated protein kinase (AMPK) and increases in mammalian target of rapamycin complex 1 (mTORC1) (13). The role of altered nutrient signaling in potentiating cyst growth has made these key targets for therapeutic innovation in ADPKD (12). At a systemic level, reduced AMPK activity is a key feature of metabolic diseases and is associated with chronic inflammation (51). Metabolic reprogramming is also connected to proinflammatory signaling in the cystic kidney. For example, the proinflammatory cytokine macrophage migration inhibitory factor (MIF) activates aerobic glycolysis (52, 53). Deletion of the gene for MIF or pharmacological inhibition of MIF lowers glucose uptake, glycolysis, mammalian target of rapamycin (mTOR) activation, and AMPK inhibition (54) and slows kidney disease progression in multiple Pkd1-deficient models (55). Persistent injury of the renal tissue by cyst growth leads to continued macrophage accumulation and proinflammatory signaling in a maladaptive cycle (54), and rodent studies have established a causal role for macrophage accumulation in ADPKD progression (56–59). Lifestyle modifications to improve systemic metabolic health and reduce chronic inflammation are therefore pertinent in ADPKD.

Dietary Interventions for ADPKD

The majority of the metabolic and signaling pathways that are perturbed in ADPKD are not specific to renal cysts. This can be problematic for drug development due to increased potential for extrarenal side effects (60). However, in cases where obesity and metabolic disease co-occur with ADPKD, these common pathways become potentially important treatment targets, many of which are amenable to dietary interventions. Dietary interventions are relatively low cost and can be combined with drug therapy, permitting a lower dose of drug and thereby reducing side effects (14). This section highlights dietary interventions that aim to challenge the aberrant metabolism contributing to cyst growth while concurrently improving systemic metabolic health.

Caloric restriction

In general, CR has wide-ranging benefits for metabolic health and longevity (61, 62). Two independent groups recently showed impressive attenuation of disease in orthologous mouse models of ADPKD. Kipp et al. (63) found that 23% CR slowed cyst growth and prevented end-stage renal disease in 2 models through inhibition of mTORC1 signaling. Warner et al. (22) further showed dose-dependent reductions in cyst growth in mice with CR of 10–40%, although 2 mo of 20% CR approached 6 mo of 40% CR in efficacy. Furthermore, CR reduced proinflammatory cytokine expression [monocyte chemoattractant protein 1 (MCP-1), IL-6, TNF-ɑ] and restored expression of the glycolytic enzyme HK2 to WT levels. When applied at a later stage, 40% CR reduced the existing cystic burden. The mTORC1-S6K pathway was inhibited and liver kinase B1 (LKB1)–AMPK activated before kidney size changed, suggesting a potential causal role for the key nutrient signaling pathways.

A recently completed clinical trial (NCT03342742; Figure 2) investigated the feasibility and tolerability of a caloric deficit of ∼34% in 30 overweight/obese adults with ADPKD. This is based on novel preliminary data that overweight/obesity are independently associated with more rapid kidney growth, consistent with prior reports (4). Constant CR will be compared to restriction by 80% of caloric needs on 3 d per week, a form of intermittent fasting (IF).

FIGURE 2.

Dietary interventions for ADPKD: preclinical studies and clinical trials to date. NCT03342742 is completed, results not yet published. Note that none of the current clinical trials are sufficiently powered to test therapeutic efficacy. Numbers in parentheses are reference citations. ADPKD, autosomal dominant polycystic kidney disease; CR, caloric restriction; IF, intermittent fasting; KD, ketogenic diet; TRE, time-restricted eating.

Intermittent fasting and time-restricted feeding

Although CR shows promise, its implementation may be challenging due to side effects (64). Adherence to a special diet may be a particular concern, and loss of bone density and lean body mass in the elderly may contribute to increased risks of frailty (65). IF and TRF are alternative dietary interventions that produce many of the same effects through the periodic activation of fasting-responsive systems, such as the AMPK pathway, without requiring constant restriction. The term IF encompasses repeated fasting periods of a day or more [e.g., alternate-day fasting (ADF)], while TRF refers to a restricted daily eating window. For example, 16:8 TRF consists of 16 h of fasting per day and an 8-h ad libitum eating window (64).

An advantage of IF or TRF as compared with traditional CR is that rigorous tracking is not required to achieve reductions in food intake. Caloric intake was spontaneously reduced in trials of TRF [by 20% (66), 300 kcal/d (67), and 550 kcal/d (68)]. Compliance may also be better with IF/TRF due to appetite-reducing effects (69–71). Following an 8-wk trial of ADF or CR in obese adults, participants in the ADF group continued to lose fat and gain lean mass during a 24-wk unsupervised follow-up period, with many indicating they had continued to fast intermittently; the same was not observed in the CR group (72). Continued adherence without monitoring is noteworthy, given that weight-loss maintenance frequently requires extensive support (73). Thus, IF or TRF may be more feasible than CR for chronic conditions, including ADPKD and metabolic disease, where long-term adherence is necessary.

Like CR, IF has an array of demonstrated benefits for metabolic health and longevity. In mice, TRF prevents obesity and metabolic disease caused by a high-fat diet (74) or a high-fat, high-sucrose diet (75). Of note, it is essential that the eating window occurs within the active phase (i.e., during the night in mice, during the day in humans) in order to observe these benefits [reviewed in (76)]. A number of clinical trials of IF showed improvements in metabolic parameters, including blood pressure (77), insulin sensitivity/glucose homeostasis (72, 78, 79), and lipids (72, 77, 80, 81), even on the background of a high-fat diet (82). Clinical trials of TRF showed similar improvements; decreased blood pressure (67) and insulin resistance and oxidative stress (68) have been observed in healthy individuals and in prediabetic men (70), and lipids and glycated hemoglobin (HbA1c) were additionally improved in metabolic syndrome (83). Notably, a daily fast of ∼17 h during Ramadan had no negative effects on kidney function in patients with ADPKD, while proteinuria decreased (84).

There is reason to predict that TRF or IF would slow ADPKD in a similar fashion to CR. Fasting was reported to inhibit aerobic glycolysis and proliferation in colorectal cancer (85). Furthermore, most rodent studies of CR are also, in practice, a form of TRF because the daily ration of food is consumed within a few hours (86). This was noted in a study showing CR efficacy in orthologous ADPKD mice (63), leading the authors to conduct the only preclinical study to date on TRF in ADPKD (87). They showed promising results with 16:8 TRF in the non-orthologous Han:SPRD-cy rat (discussed below in “Preclinical evidence in ADPKD”). Future studies are required to replicate these results in orthologous models and test other IF regimens. A clinical trial of 8-h TRF in overweight or obese adults with ADPKD is currently underway (NCT04534985; Figure 2).

Ketogenic diet

Part of the adaptive response to fasting involves the metabolic switch to production and utilization of ketone bodies like β-hydroxybutyrate (BHB) and acetoacetate. In humans, fasting concentrations of BHB were elevated by 18:6 TRF (88), while BHB concentrations not only surge on fasting days but remain elevated throughout an ADF regimen (81). Ketogenesis can also be induced without fasting or CR through adherence to a high-fat, very-low-carbohydrate KD. Mounting evidence suggests that the KD also increases longevity (89, 90) and may benefit cases of obesity and metabolic disease [reviewed in (91, 92)].

The KD has been used to treat childhood epilepsy since the 1920s (93). From research in epilepsy, the safety and efficacy of the KD have been demonstrated in children (94, 95) and adults (96, 97). Furthermore, a hypocaloric KD has been demonstrated to be safe and effective for weight loss in obese individuals with mild kidney failure (stage 2 chronic kidney disease), nearly a third of whom had improved renal function after the 3-mo intervention (98). These results support the potential safety of the KD as an early intervention in ADPKD or in patients with comorbid obesity and metabolic disease.

The KD may have particular advantages for weight loss compared with conventional CR. In the context of overweight/obesity and type 2 diabetes, a hypocaloric KD was superior to standard CR for weight loss and glycemic control (99, 100). For weight loss in general, a low-fat diet or KD are equally effective given equal caloric intake; however, long-term compliance may be better with a KD due to its appetite-reducing effects (101–104), which counteract the increase in appetite that accompanies weight loss (105, 106). Thus, akin to IF/TRF, the KD presents advantages over conventional CR for weight loss and holds promise for addressing the intersection of ADPKD and obesity.

Preclinical evidence in ADPKD

Recently, Torres and colleagues (87) published evidence that inducing ketosis—whether by KD, TRF, acute fasting, or exogenous ketones—greatly improved the phenotype of 3 animal models of ADPKD. The most extensive evidence was in the non-orthologous Han:SPRD rat model. After 5 wk of isocaloric 16:8 TRF or ad libitum KD, relative kidney weight, cystic index, and epithelial proliferation were reduced; KD additionally reduced fibrosis and mTOR signaling, and increased creatinine clearance. Exogenous BHB (in the drinking water at 157.5 mM concentration) with normal chow produced similar effects. The KD also decreased kidney and cyst size, although not cyst number, in established disease, an effect that has previously only been seen with CR (22) or mTORC1 inhibition using high-dose rapamycin (60, 107).

Remarkably, a single acute 48-h feed deprivation reduced cystic kidney weight proportionately more than the weight changes in other organs or in WT kidneys, and cell death was increased selectively in cyst-lining cells of mutant kidneys (87). Lipid droplets accumulated within the cyst-lining cells, consistent with previous reports of defective FAO (21, 47, 108). Lipid-induced toxicity (lipotoxicity) in cyst-lining cells may be responsible for the increase in cell death. This weakens the epithelial barrier and allows cyst drainage, perhaps explaining the reductions in cyst size but not number. This was supported by increased cyst-lining cell death after 24-h feed deprivation in orthologous (Pkd1) mice, and a decrease in total kidney volume (TKV) and apparent cyst drainage after 72-h feed deprivation in naturally occurring orthologous PKD1 mutant Persian cats. These results are remarkable and need to be replicated independently.

Torres et al. (87) reported a minor increase in BHB concentrations on TRF, while others have reported that CR, but not TRF (1 meal/d), induced ketosis in mice (109). It will be important to distinguish whether the benefits of CR (22, 63) or TRF (87) in ADPKD are indeed primarily mediated by ketosis. Larger studies in orthologous animals are needed. Nevertheless, the results of these preclinical studies are promising and have led to the initiation of clinical trials.

Clinical trials

A phase II trial of the modified Atkins diet (MAD) in patients with rapidly progressive ADPKD is currently underway (110) (Figure 2). The MAD, which, unlike the classical KD, permits unrestricted intake of protein, fluids, and calories, was first introduced to induce ketosis in the outpatient setting (111) and has better compliance compared with the classical KD (112). This follows a small pilot study in which 3 mo of MAD (prescribed 20 g carbohydrate/d) was well tolerated, glycemia decreased over the study period, and BHB concentrations were consistently elevated (113). Transient side effects were minor and predictable (114). Total cholesterol increased, as has been previously reported with the KD (115, 116). However, KD-induced dyslipidemia may resolve in the longer term (117–119), and after 10 y of follow-up, the KD did not alter cardiovascular risk in other clinical settings (120). An independent group is currently recruiting for a trial of ketogenic dietary interventions in 63 patients with rapidly progressive ADPKD (NCT04680780). Patients will be randomly assigned to 3 mo of the classical KD, 3 mo with a 3-d water fast within the first 2 wk of each month, or a control arm. Adherence (ketone concentrations) and subjective feasibility will be measured, along with secondary outcomes including TKV and BMI.

Ketosis—potential mechanisms

Evidence that cystic epithelia are glucose-dependent and success in preclinical models with 2DG administration (reviewed above) suggest that the KD acts, in part, by limiting glucose availability. However, ketosis-inducing interventions (e.g., TRF, oral BHB) did not consistently decrease blood glucose concentrations, even though they improved the phenotype of Han:SPRD rats (87). In CR, serum glucose only trended downwards, and kidney glucose transport protein 4 (GLUT4) expression was upregulated, potentially compensating the reduced serum glucose (22). Nevertheless, in nondiabetic patients with ADPKD, higher serum glucose concentrations predicted a greater yearly increase in height-adjusted TKV (87, 121), suggesting that reducing glucose is advantageous. This has been achieved with the KD or IF/TRF in humans [e.g. (83, 91, 92)], and although BHB supplementation does not alter fasting blood glucose (122), it does lower blood glucose acutely (123) and reduces postprandial glucose excursions in healthy (124) and obese (125) adults.

The KD redirects full-body metabolism away from glucose oxidation, inducing a rapid and lasting switch to fat oxidation (126). As part of this metabolic switch, the KD also activates AMPK (87, 127, 128), induces PPAR⍺ and several of its target genes (129–131), and affects mTORC1 signaling in a tissue-dependent fashion (89, 132). Importantly, ketone bodies provided to kidney cortex ex vivo were used preferentially, providing up to 80% of the respiratory fuel (133). A pilot study with ¹¹C-acetoacetate positron emission tomography confirmed the kidney actively consumes exogenous ketones, with uptake greater than that of the brain (134). Furthermore, BHB may inhibit cyst cell glycolysis, as has been shown in tumor cells (135), neurons (136), and heart and muscle (137). Thus, ketone bodies may sustain healthy tubular epithelia, while inhibition of glycolysis and a build-up of nonfermentable fuels reduce cyst cell growth and survival.

The common feature between CR, fasting, and the KD is elevation of BHB. In addition to providing a nonfermentable fuel to the kidney, BHB has signaling functions. It is one of few ligands for G-protein–coupled receptor GPR109A (138), the activation of which in kidney podocytes reduced inflammation and proteinuria (139); therefore, BHB may attenuate podocyte injury observed in early-stage ADPKD (140). GPR109A also has tumor-suppressor function in multiple tissues (141). Moreover, BHB is an inhibitor of class I histone deacetylases (HDACs 1–3 and 8) (142, 143) and therefore participates in a network of epigenetic regulation in ADPKD [reviewed in (144)]. Treatment with valproic acid, a class I HDAC inhibitor, inhibited cystogenesis in Pkd1 knockout mice (145). Additionally, HDACs deacetylate a number of non-histone proteins including c-MYC (146), the upregulation of which is a hallmark of ADPKD (147), and the tumor suppressors retinoblastoma protein (Rb) and p53 (148).

The regulation of p53 acetylation by BHB may be particularly important. Hypoacetylation of Rb and p53 increased proliferation and decreased cell death of the cystic epithelia, respectively (149). Mice with mutated p53 develop a renal cystic phenotype and metabolic abnormalities reminiscent of PKD (150), and it was recently shown that mTOR signaling contributes to uncontrolled growth in ADPKD cells by causing p53 degradation (151). However, in a small (n = 36) pilot trial of nicotinamide, an inhibitor of the sirtuin HDACs, temporary increases in p53 acetylation reverted within 6–12 mo (152). It is possible that BHB reverses the hypoacetylation of p53 to increase apoptosis of cystic cells. Such a mechanism could contribute to cystic cell death by fasting (87). Indeed, 1 mo of a KD increased acetyl-p53 by 10-fold in the mouse liver (89). On the other hand, BHB also causes β-hydroxybutyrylation (153), a post-translational modification shown in vitro to interfere with p53 acetylation (154). Potential p53-mediated effects of BHB in the polycystic kidney are a topic for future investigation.

BHB may also attenuate oxidative damage, which is increased in PKD and induces cyst growth (155, 156). Several antioxidant systems rely on NAD(P)H as an electron donor (glutathione, thioredoxin), and BHB reduces free cytoplasmic NADP+ to NAD(P)H (157). Additionally, BHB may reduce production of and directly scavenge mitochondrial reactive oxygen species [ROS; reviewed in (158)]. Elevation of BHB (through fasting, CR, or supplementation) protected kidneys against chemically induced oxidative damage (142, 159), in part through activation of antioxidant response regulator nuclear factor-erythroid factor 2–related factor 2 (Nrf2) (159). Nrf2 is also known to positively regulate mitochondrial biogenesis (158, 160), which is disrupted in ADPKD (12, 13). ROS production correlated with disease severity and inversely correlated with NRF2 abundance in human ADPKD; and in an orthologous mouse model, Nrf2 deletion increased, whereas Nrf2 induction decreased ROS production and cyst growth (161).

Other dietary considerations

Dietary fat

In contrast to the apparent benefits of the KD, increased fat intake appears to have detrimental effects in ADPKD when carbohydrate intake is not limited. In Pkd1^-/- mice, FAO is dysfunctional, and a minor increase in the fat content of the diet (5.62–7.47%) fed to nursing mothers and young pups resulted in minor but significant increases in relative kidney weight (21). Feeding non-orthologous Han:SPRD-cy rats or pcy mice a diet higher in fat (20 g vs. 5 g/100 g) worsened the renal phenotype (162–164), although the fat intake achieved was much greater than that of a typical human diet (165).

Several studies have also examined the effects of fat source and generally reported improvements with omega-3-rich oils (Table 1). However, these studies were in non-orthologous rodent models, and benefits were not substantiated in orthologous mice (166). Certain fats were thought to confer benefits by altering the profile of oxylipins (bioactive lipid metabolites); however, in orthologous models, dietary effects on oxylipins were found to be independent of disease severity (167). This may be due to their complex role; signaling by the oxylipin prostaglandin E2 (PGE2) stimulated cystogenesis and proliferation in vitro, but its antagonism increased inflammation and worsened disease in Pkd1-deficient mice (168). Although omega-3 PUFAs support overall metabolic health (169, 170), recommendations to consume specific fatty acids for ADPKD are not well supported.

TABLE 1.

The effects of dietary fat composition and level on ADPKD¹

	Dietary fat	Duration	Outcomes	References
Non-orthologous
Han:SPRD-cy rat	Flax vs. soybean oil	8 wk	↓ serum creatinine↓ cyst growth↓ fibrosis↓ macrophage infiltration↓ epithelial proliferation (F only)	Ogborn et al., 1999; 2002; 2006 (171–173)
	Fish vs. soybean or cottonseed oil	6 wk	↓ kidney size↓ fluid content↓cyst volumesvs. cottonseed only:↓ fibrosis↓ inflammation	Lu et al., 2003 (164)
	Flax vs. corn oil	7 wk + perinatal period (fed to mother 2 wk prior to conception until weaning)	↓ cyst growth↓ epithelial proliferation↓ oxidant injury↓ fibrosis↓ glomerular hypertrophy↓ proteinuria↑ serum urea↑ serum creatinine	Sankaran et al., 2006 (174)
	Fish vs. soybean oil	8 wk	No effect Altered eicosanoids	Ibrahim et al., 2014 (175)
Han:SPRD-cy rat (162, 164),pcy mouse (163)	Fat level:Low (4–5 g/100 g) vs. high (20 g/100 g diet)Soybean oil (162–164)Fish oil (164)Cottonseed oil (164)	6 wk (162, 164)130 d (163)	↓ kidney weight (162–164)↓ fluid content (162)↓ cyst score (162)↓ serum urea (162, 163)↓ fibrosis (163, 164)↑ creatinine clearance (M only) (162, 164)	Jayapalan et al., 2000 (162)Lu et al.,2003 (164)Sankaran et al., 2004 (163)
pcy Mouse	EPA-enriched vs. sunflower seed vs. standard	60 d	↓ tubular dilation↓ cyst area (M only)	Yamaguchi et al., 1990 (176)
	Fish oil vs. sunflower seed oil	Ad mortem	No effect (on proteinuria or survival) Altered renal fatty acid composition	Aukema et al., 1992 (177)
	Flaxseed vs. algal vs. corn oil	8 wk	Flaxseed oil mitigated increased fibrosis with higher fat level Algal vs. corn oil↑ kidney weight↑ cyst volume	Sankaran et al., 2004 (163)
Orthologous
PCK rats (ARPKD)	Soybean/salmon oil blend vs. soybean vs. corn oil	12 wk	No effect (on kidney weight, cyst size, inflammation, or fibrosis)	Maditz et al., 2013 (165)
Pkd2WS25/- mice (ADPKD),PCK rats (ARPKD)	Flax vs. fish vs. soybean oil	12–13 wk	No benefit Pkd2WS25/-: fish oil↑ kidney size↑ fluid content PCK: fish and flax oil↑ kidney size↑ fluid content↑ cyst area	Yamaguchi et al., 2016 (166)
Clinical trial
n = 41 patients with ADPKD,age 47 ± 12 y, stage 2–3 CKD	EPA capsules 2.4 g/d vs. no supplement No placebo control	2 y	No effect (on kidney volume or creatinine clearance)	Higashihara et al., 2008 (178)

¹Benefits of lower fat intake and of replacement with omega-3 fatty acid-rich sources were observed in non-orthologous rodent models. However, these results were not replicated in orthologous models, and a clinical trial of supplemental EPA showed no benefit. ADPKD, autosomal dominant polycystic kidney disease; ARPKD, autosomal recessive polycystic kidney disease; CKD, chronic kidney disease; Pkd2, polycystin 2.

Protein restriction

Studies have also investigated the effect of protein source on ADPKD progression. Most report better outcomes with soy (plant) compared with casein (animal) protein (Table 2). However, this evidence again comes from non-orthologous models and was not replicated in orthologous rodents (166). Furthermore, in a large study of 200 patients with ADPKD, a low-protein diet [0.58 g/(kg/d)] showed no protective effect for a glomerular filtration rate (GFR) range of 25–55 mL/(min/1.73 m²) (179). A study following 589 patients with ADPKD for 4 y found no association between protein intake and annual change in estimated GFR (180).

TABLE 2.

The effects of dietary protein source and level on ADPKD¹

	Dietary protein	Duration	Outcomes	References
Non-orthologous
Han:SPRD-cy rat	Soy vs. casein	6–8 wk	↓ serum creatinine↓ cyst size↓ fibrosis↓ macrophage infiltration↓ epithelial proliferation	Ogborn et al., 1998 & 2000 (181, 182)
		6 wk	↓ kidney weight↓ fluid content↓ cyst size↓ serum urea and creatinine	Aukema & Housini, 2001 (183)
		1–3 wk	1 wk:↓ fibrosis↑PGE23 wk:↓ cyst growth	Fair et al., 2004 (184)
		7 wk + perinatal period (2 wk preconception to weaning)	↓ macrophage infiltration↓ epithelial proliferation↓ proteinuria	Cahill et al., 2007 (185)
		4 mo (began at 2 mo of age)	↓ epithelial proliferation↓ oxidative damage ↓ inflammation	Sankaran et al., 2007 (186)
		8 wk	↓ cyst growth↓ fibrosis↓ COX products↑ LOX products	Ibrahim et al., 2014 (175)
	Protein level: high (50%) or low (4%)vs. control (23%) casein	6 wk	High protein increased, low protein decreased relative kidney weight	Cowley et al., 1996 (187)
pcy Mouse	Protein level: low (6%) vs. control (25%)casein	105 d	↓ relative kidney weight↓ fluid content↓ cyst area	Tomobe et al., 1994 (188)
	Soy vs. casein	90 d	↓ relative kidney weight↓ fluid content↓ cyst volume	Tomobe et al., 1998 (189)
		13 wk	Only if low protein (6% vs. 17.4%):↓ relative kidney weight (F only)↓ fluid content↓ cyst score	Aukema et al., 1999 (190)
Orthologous
PCK rat (ARPKD)	Soy vs. casein	12 wk	No effect (on relative kidney weight, cyst size, inflammation, or fibrosis)	Maditz et al., 2013 (165)
Pkd2WS25/- mice (ADPKD),PCK rats (ARPKD)		12–13 wk	No effect	Yamaguchi et al., 2016 (166)
Clinical trial
n = 141 patients withADPKD, GFR13-24 mL/(min/1.73 m²)	Protein level: low-protein diet0.58 g/(kg/d) vs. usual-protein diet 1.3 g/(kg/d)	Mean 2.2 y follow-up	No effect (rate of GFR decline)	Klahr et al., 1995 (179)

¹Benefits of plant vs. animal protein and lower protein intake were observed in non-orthologous rodent models. However, plant protein conferred no benefit in orthologous rodent models, and a low-protein diet did not reduce rate of GFR decline in a clinical trial. ADPKD, autosomal dominant polycystic kidney disease; ARPKD, autosomal recessive polycystic kidney disease; COX, cyclooxygenase; GFR, glomerular filtration rate; LOX, lipoxygenase; PGE2, prostaglandin E2; Pkd2, polycystin 2.

While evidence supporting severe protein restriction is lacking, excessive protein intake may be detrimental. In an orthologous mouse model, supplementation with branched-chain amino acids upregulated mTORC1 and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling, increasing proliferation of cyst-lining cells (191). Moreover, excessive protein increases systemic acidity, osmolarity, and the nitrogenous waste burden on the kidney. A low osmole diet (protein 0.8–0.9 g/kg and sodium 1500 mg/d) suppressed ambulatory venous presure (AVP) (192, 193), although perhaps not enough to be clinically relevant (194). Considering the available evidence, moderate intake sufficient to meet nutritional needs should be emphasized, and avoidance of excess protein is advisable, as has also been concluded by others (195). This recommendation should be considered when implementing a low-carbohydrate, unrestricted protein diet such as the MAD.

Conclusions

Obesity and metabolic disease are increasingly common conditions with important implications for the progression of ADPKD. Abnormalities in metabolic regulation observed in the cystic kidney share common features with systemic changes observed in individuals with metabolic disease and associated with obesity, including alterations in nutrient-signaling pathways and the activation of chronic inflammation. The intersection of local and systemic metabolic abnormalities is a compelling treatment target in ADPKD with comorbidities such as obesity and/or metabolic disease. The diet is a pivotal point of intervention to this end, with the potential to improve systemic metabolic health while also preferentially targeting cyst-lining cells, which are vulnerable to changes in substrate availability. While investigations of the role of metabolism in ADPKD have focused on abnormalities in basic metabolic processes, including aerobic glycolysis, glutamine dependence, and impaired FAO, evidence from dietary intervention studies underlines the importance of further investigation into the role of ketosis in cyst metabolism and growth. Dietary regimens including CR, IF, and KDs have shown promise in slowing ADPKD progression in animal models. While caution is necessary when interpreting the results of preclinical studies, especially in non-orthologous animal models, clinical trials currently underway promise to improve our understanding of the impact of diet on ADPKD.

Patient adherence may limit the feasibility of a dietary approach to treating ADPKD. However, the majority of patients with ADPKD are highly motivated to implement lifestyle-based interventions, particularly when recommendations are clear and well-supported (196). Questions remain regarding the timing of interventions, although preclinical data suggest benefits even at later stages of disease. Monitoring to ensure adequate nutrition is important, especially in cases of existing renal functional impairment. This further emphasizes the need for dietary interventions to be discussed within the clinical setting to ensure proper formulation.

The implementation of dietary interventions and their mechanisms of action are of particular interest in light of the increasingly common presentation of ADPKD with comorbid obesity or metabolic disease. Indeed, many features of metabolic disease intersect with local metabolic abnormalities in the cystic kidney, pointing to critical pathways for therapeutic intervention.

Although dietary interventions seem especially suited to individuals with ADPKD who would also benefit from weight loss, the main mechanisms of benefit—altered nutrient availability and signaling in the cystic kidney, and systemic improvements in metabolic health—would also be expected to occur in normal-weight individuals. The results of adequately powered clinical trials in normal-weight and obese individuals with ADPKD are eagerly awaited.

Notes

Supported, in part, by the Canadian Institutes of Health Research (CIHR; PJT-162083) of Canada and Sun Life Financial New Investigator Award of Banting & Best Diabetic Centre (BBDC), University of Toronto (to H-KS). Also partly supported by the CIHR Strategy for Patient Oriented Research (SPOR) program grant in Chronic Kidney Disease (CAN-Solve-CKD SCA-145103; to YP).

Author disclosures: YP received compensation for participation in advisory boards for Otsuka, Sanofi-Genzyme, and Reata Pharmaceuticals. The other authors report no conflicts of interest.

Abbreviations used: ADF, alternate-day fasting; ADPKD, autosomal dominant polycystic kidney disease; AMPK, AMP-activated protein kinase; BHB, β-hydroxybutyrate; CPT, carnitine palmitoyltransferase; CR, caloric restriction; FAO, fatty acid oxidation; GFR, glomerular filtration rate; GLS, glutaminase; HDAC, histone deacetylase; HK, hexokinase; Hnf4a/HNF-4ɑ, hepatocyte nuclear factor 4ɑ; IF, intermittent fasting; KD, ketogenic diet; MAD, modified Atkins diet; MEF, mouse embryonic fibroblast; MIF, macrophage migration inhibitory factor; mTOR, mammalian target of rapamycin; mTORC1, mammalian target of rapamycin complex 1; Nrf2, nuclear factor-erythroid factor 2-related factor 2; OXPHOS, oxidative phosphorylation; Pkd, polycystin; PPARa, peroxisome proliferator activated receptor ɑ; Rb, retinoblastoma protein; ROS, reactive oxygen species; TKV, total kidney volume; TRF, time-restricted feeding; WT, wild-type; 2DG, 2-deoxyglucose.