Most of the nutritional suggestions for the management of chronic kidney disease (CKD) in autosomal polycystic kidney disease (ADPKD) in ADPKD derive from the general recommendations for CKD due to different etiology in particular.

Proper protein intake can help prevent or improve part of the metabolic imbalances due to chronic kidney disease. Prescription of a low-protein dietary regime remains one of the most widely used strategies for the management of symptoms related to uremic toxicity in CKD patients. The amount of protein is defined by the CKD stage: (Table 1) stages 1, 2, and 3a 0.8 g/kg/day; at stage 3b, protein restriction is 0.6 g/kg/day; at stages 4 and 5, this is 0.6 g/kg/day or 0.4–0.3 g/kg/day with amino acids or ketoanalogues supplementation ^[1][19].

Protein restriction has been proven to delay evolution to ESKD in non-autosomal polycystic kidney disease (ADPKD) CKD patients, as shown in the Modification of Diet in Renal Disease (MDRD) study ^[2][20] where it was demonstrated that a low protein diet results in a slower decline in glomerular filtration rate (GFR). Studies in ADPKD patients have failed to demonstrate the slowing of CKD progression, as shown in the analysis of data from the ADPKD cohort of the MDRD study, Kramers et al.’s study, and the CRISP study ^[2][3][4][20,21,22].

The CRISP study initially showed an association between total kidney function increase and GFR decline and protein intake; however this association was not confirmed after adjustment for important confounders ^[4][22].

An elegant work conducted by Heida et al. showed a strong association between a high urine-to-plasma urea ratio and GFR decline in polycystic adult patients. Considering that the urine-to-plasma urea ratio positively correlates with protein intake, such a result suggests how low protein consumption could slow the worsening of kidney function even in ADPKD patients ^[5][23].

However, the majority of experts suggest the avoidance of very low protein intake (<0.6 g/kg/die) for malnutrition risk and suggest that if a similar regimen is adopted there be strict and careful monitoring of patients with trimestral or at least semestral follow-up ^[6][24].

Due to the lack of strong evidence, there is not a widely accepted guideline on protein intake in ADPKD patients and neither does the KDIGO Controversies Conference on ADPKD specify a protein regime ^[7][4]. The KDOQI guidelines for nutrition in CKD recommend protein restriction but without a specific evaluation of polycystic patients ^[7][4].

The importance of lowering salt intake is a priority in CKD patients. The aim is to keep sodium intake lower, to 90 mmol/day, corresponding to the consumption of less than 2000 mg/day of sodium (Na) and <5 g/day of sodium chloride (NaCl). This leads to better management of blood pressure, limitation of kidney damage, and a better cardiovascular outcome ^[8][25].

Phosphate homeostasis abnormalities are frequently observed in patients with reduced kidney function and are often predictive of negative clinical outcomes. Hyperphosphatemia contributes to the burden of cardiovascular disease leading to cardiovascular and soft-tissue calcifications, cardiac disease, renal osteodystrophy, and secondary hyperparathyroidism. Phosphorus requirements depend on the stage of CKD and should consider the avoidance of malnutrition, not unusual in ESKD and dialysis patients ^[9][26].

Kidney’s potassium excretion is reduced with the lowering of the glomerular filtration rate, and hyperkalemia is a severe condition commonly experienced by CKD patients. Monitoring of potassium serum levels is fundamental, and the target values are 3.5–5.0 mmol/L to be reached with lower potassium diets and, if necessary, with hypokalemic drugs ^[9][26].

High protein intake is associated with hyperfiltration secondary to the secretion of glucagon, strictly associated with gluconeogenesis in the liver and with urea excretion by the kidneys, together with cAMP released from the liver. A protein-rich meal induces simultaneous vasopressin release improving urine concentrating ability, as shown in some studies on healthy humans in which GFR after high protein intake significantly correlates with increasing urine osmolality. The two hormonal pathways lead to increased urea excretion and water reabsorption, reducing the tubuloglomerular feedback (TGF) signal at macula densa and then increasing GFR, inducing hyperfiltration ^[10][27]. This mechanism, linked to vasopressin release, can at least partially explain the reduction in cystogenesis observed by reducing protein intake.

Indeed, in a study on DBA/2FG-pcy (pcy) mice, Aukema et al. showed how a low protein regimen has a positive impact in reducing cyst growth and kidney volume in comparison with a normal protein diet ^[11][28]. The same authors also demonstrated that dietary protein source and sex also affect size and fluid content in polycystic kidneys. In this researchtudy, the pcy mice were divided into two groups, a low protein regimen and a normal protein regimen; both groups were divided into two subgroups. In one, the animals were fed with soy protein isolate and in the other, the animals were fed with casein. The results show that the kidney weights were 28% lower in the animals fed with the low-protein regime based on soy compared to the mice consuming the casein-based diet, as the area of the parenchyma occupied by cysts was also 19% lower in the same group ^[12][29].

Vasopressin (AVP) stimulates cyst growth in ADPKD. Increased water intake is recommended for AVP secretion suppression, which reduces AMPc synthesis and consequently cyst growth ^[13][7] and improves kidney function, as shown in experiments on ADPKD mice ^[14][15][30,31]

The DRINK study explored a high-water intake regimen in humans as an alternative to pharmacological therapy in blocking vasopressin. The patients were divided into two groups: high water intake (HW) and ad libitum intake (AW); the 8-week experiment showed that the osmolarity target (<270 mOsm/kg) could be reached by the majority of the patients in the HW intake group without difficulty, demonstrating the feasibility, safety, and adherence to a possible water therapy ^[16][32].

Another study published by Rangan et al. in 2022 studied two groups of ADPKD patients, one with high water intake versus one with ad libitum intake, and even though a reduction in urinary osmolarity was observed in the high-intake group, no differences in kidney volume emerged ^[17][33].

What is important to underline is the necessity of further trials to verify the effects of water intake on the progression of ADPKD.

Otherwise, increased water intake has also been shown to counteract nephrolithiasis, reducing the risk of stone formation, one of the main comorbidities of ADPKD ^[18][34].

Sodium restriction in ADPKD may be favorable because of the reduction in renin angiotensin aldosterone system activity. Aldosterone induces the transcription of the alpha subunit of Na/K ATPase which may promote, in ADPKD patients, fluid secretion and cyst enlargement. In addition, through the epidermal growth factor receptor, it stimulates kidney fibroblast proliferation and the proliferation of dedifferentiated kidney tubule cells ^[19][35].

Additionally, blood pressure control has been demonstrated to be fundamental in disease progression. As with the other causes of CKD, even in ADPKD patients, strict management leads to a slower reduction in GFR and a lower annual increase in kidney volume ^[20][36].

T restriction also reduces vasopressin levels. Amro et al. ^[21][37] performed a two-week randomized trial to determine whether a low-sodium (1500 mg/day) and normoproteic (0.8 g/kg) diet, with adjusted water intake, would suppress AVP secretion in 34 ADPKD patients. The patients were randomly divided into intervention and control groups, and plasma copeptin and urinary osmolarity levels were used as indicators of AVP suppression. At the end of the observation period, there was a significant decrease in the intervention group for both values: copeptin decreased from 6.2 ± 3.05 to 5.3 ± 2.5 pmol/L (p = 0.02), and urinary osmolarity decreased from 426 ± 193 to 258 ± 117 mosm/kg (p = 0.01), while they remained unchanged in the control group. Thus, suppression of AVP is also possible by managing sodium intake and without large increases in water intake, which may be more difficult to maintain in the long term.

Furthermore, in Hane:SPRD mice (a model for polycystic kidney disease), an increase in sodium intake is accompanied by a higher kidney weight and cyst dimension ^[22][38].

However, the literature on randomized trials investigating the effect of a reduction in salt intake in the progression of ADPKD disease is scarce. The best evidence available is from a post hoc analysis of the HALT A and B trials where the effect of blood pressure control and RAAS blockade was investigated in ADPKD. In particular, the post hoc analysis showed that a decrease of 1 g in salt intake is associated with a reduction in kidney growth (0.43%/year) and GFR decline (−0.09 mL/min/1.73 m²/year for each gram of salt reduction) and also with a lower incidence of composite renal endpoint (reduction of eGFR of 50%, ESKD or death) ^[23][39]. In conclusion, the data suggest a beneficial effect of sodium restriction in the management of ADPKD.

High phosphate levels in ADPKD could induce tubular injury, promoting cyst growth and disease progression.

Omede et al. suggested that restriction in the dietary intake of phosphates may be able to slow cystic development and fibrosis in PKD. To verify this, the authors divided the PKD mice into two identical groups and fed them with two regimes differing only in phosphate intake (normo-phosphoric and hypo-phosphoric). Dietary phosphate restriction resulted in a 25% lower kidney weight/body weight ratio, a reduction in the number of cysts, and expression of tubular injury markers (neutrophil gelatinase-associated lipocalin—NGAL) ^[24][40].

Caffeine is a methylxanthine that increases the levels of intracellular cAMP in cultured renal ADPKD epithelial cells. A retrospective analysis of the CRISP study cohort found no association between caffeine consumption and a higher increase in hTKV (height-adjusted total kidney volume), progression to ESKD, or death in 239 patients with an average follow-up of 12.5 years ^[25][41]. Even data from a prospective longitudinal study that analyzed caffeine consumption and kidney volume and function did not find an association ^[26][42]. Secondary to the absence of strong evidence, the limitation in caffeine consumption in ADPKD patients is limited to general suggestions ^[7][4].

Appropriate nutrients and calorie intake must always be reached in order to avoid malnutrition and related complications ^[27][18]. Caloric restriction under the supervision of doctors and dietitians is desirable if weight loss is necessary for either the general population or in CKD patients.

There are currently few studies concerning the association between overweight/obesity and the decline of kidney function in ADPKD. Nowak et al. investigated this correlation by analyzing data from 441 non-diabetic participants in the HALT PKD study A with early ADPKD ^[28][43]. The subjects were divided into normal weight, overweight, and obese based on BMI (body mass index) calculated excluding the weight of the kidneys and liver. A higher BMI was associated with a greater increase in TKV over time (normal weight: 6.1% ± 4.7%, overweight: 7.9% ± 4.8%, and obese: 9.4% ± 6.2%; p < 0.001) after a follow-up of five years. This could be due to continuous caloric excess, leading to strong activation of the mTOR pathway with relative suppression of AMPK (adenosine monophosphate-activated protein kinase), leading to the proliferation of cysts. Following this hypothesis, it has been thought that slight/moderate calorie restriction, activating AMPK and suppressing mTOR, could slow the progression of the disease ^[29][44]. This has been verified in animal model experiments. For example, Kipp et al. ^[30][45] showed how, in an orthologous mouse model of ADPKD, a reduction in food intake by 23% slows disease progression without affecting body weight or causing malnutrition or any side effects. An interesting and elegant experiment conducted by Hopp and colleagues ^[31][46] investigated the feasibility of daily caloric restriction (DCR) and intermittent fasting (IMF) in overweight ADPKD patients, showing significant weight loss and a reduction in cyst growth even with DCR and IMF, although DCR was more tolerated. In parallel, they compared the efficacy of DCR, IMF, and time-restricted feeding (TRF) in the ADPKD mouse model and they found that only mice on DCR had significant weight loss and slowing down of cyst growth. Even this work confirms the benefit of weight loss in ADPKD progression on human and on mice and emphasizes the feasibility of a daily caloric restriction regimen.

The beneficial effects of food restriction in several aspects of health appears to be related to the insulin growth factor-1 (IGF-1) pathway, which is also dysregulated in cancer and aging. In ADPKD, IGF-1 could be involved in cyst proliferation; in fact, some studies have found increased expression of IGF-1 in polycystic patients and animal models ^[32][47]. The work of S. Kashyap et al. ^[33][48] identified PAPP-A, a metalloprotease that cleaves IGF-1 binding protein and frees IFG-1, as a crucial factor in increasing IGF-1 bioavailability and which opens new future research for understanding ADPKD pathological mechanisms and for discovering new therapeutic targets.

In addition to the classic diet approach, interesting new strategies are being increasingly studied, such as calorie restriction or diets inducing ketosis states.

A KD is carried out with careful food planning, with macronutrients in predetermined proportions. The classic approach is based on the lipid ratio which can vary from a four parts fat (long-chain triglycerides) to a one-part combined protein and carbohydrate ratio (from 4:1 to 2:1), supplemented with minerals and vitamins ^[34][49].

Nowadays, in addition to the classic KD mentioned above, there are new approaches able to induce a ketogenic status, more tolerated in the long-term, such as the modified Atkins diet, the MCT diet, or versions of intermittent fasting (for example time-restricted feeding), which are commonly used in daily practice.

Recent studies ^{[30][35][36][37]}[45,50,51,52] have shown that a diet able to induce moderate calorie restriction, such as time-restricted feeding (TRF) or classical intermittent fasting, may be effective in counteracting cyst growth. The first experiment was carried out on animal models of PKD; the results showed that a moderate calorie restriction regime led to a reduction in the size and growth rate of cysts and inflammation levels. The mechanism responsible for the positive effect of the restriction is thought to be the inhibition of the mTOR transduction pathway, which in ADPKD is pathologically hyperactive, leading to cyst growth and forced inhibition of AMPK. Under calorie restriction conditions, the ATP/AMP ratio decreases, leading to activation of AMPK, inhibition of mTOR, and then to a correct balance between AMPK and mTOR.

The potential benefits of ketosis in ADPKD have recently been discovered and for this reason, there are very few clinical trials published or in progress concerning the ketogenic regimen in humans ^[38][39][40][58,59,60] and they are all preliminary studies with an extremely small cohort of patients. One of these is the Ren.nu program published by Bruen et al. It is a 16-week duration protocol with the aim of educating patients, through interviews with dietitians, to adopt and maintain a modified and plant-focused ketogenic diet ^[39][59]. The energy needs were calculated patient-based, with the macronutrients divided into 10–15% net CHO (total carbohydrates minus fibers), 10–15% PRO (protein), and 70–75% FAT (lipid), which avoids the excess of oxalates, phosphates, and uric acid and includes the use of a special supplement containing mainly BHB and citrates ^[39][59]. In addition to nutrition management, the patients were also trained to control the status of ketosis through monitoring their serum ketone levels. A first beta test phase with 24 selected participants ended in 2021; 20 participants completed the test and submitted questionnaires verifying the feasibility, tolerance, and adherence to the program. The results show improvements in terms of pain and general fatigue related to the disease, with good satisfaction regarding nutrition. The main issues were the side effects of ketosis and difficulty with eating in restaurants. Finally, the anthropometric measures, blood tests, and kidney function values were analyzed at the end of the experiment and compared with the basal values. The results showed an average weight drop of 5.6% (−4 kg), an average decrease in fasting blood sugar of 16.5% (−19 mg/dL), and a mean creatinine drop of 5.8% (−0.1 mg/dL) with an eGFR increase of 8.6% (+4.4 mL/min/1.73 m²). As mentioned before, even this work has the limitation of evaluating kidney function with the measure of creatinine and estimation of the glomerular filtration rate.

A study by Testa et al. tested the feasibility and potential benefits of a modified Atkins diet in ADPKD patients ^[40][60]. The choice of this scheme is due to its greater flexibility, which is why it is thought to be more applicable in the long term. The study lasted three months, three patients were enrolled, and macronutrients were calculated and divided based on the energy needs of patients with 5% CHO, 30% PRO, and 65% FAT. At the end of the experiment, the subjects completed questionnaires that revealed high satisfaction with the regimen and strong compliance, with only a few problems, concerning mainly the difficulties at restaurants and side effects due to the induction of the ketosis state. They observed an average increase in total cholesterol of 34 ± 13.1 mg/dL but it is not specified if the regimen prescribed was with specific ketogenic bar products or with fresh food, which could explain the increase in the cholesterol values. On the other hand, they found a decrease in blood sugar from 105.8 ± 8.5 mg/dL to 92 ± 8.8 mg/dL, and overweight patients (two of the three involved in the study), who were given a slightly low-calorie protocol, obtained a weight loss of 4.2 kg for one patient and 1 kg for the other. There was no change in kidney function.

Another interesting study, the first prospective interventional trial, RESET-PKD ^[41][61], confirms that KD induces ketogenesis which leads to a rapid change in total liver volume without modification to TKV. The authors suggest that the lack of response in kidney volume was secondary to the short duration of the intervention.

New randomized controlled clinical trials are currently ongoing and are evaluating time-restricted feeding ^[42][62], calorie restriction ^[43][63], and ketogenic dietary intervention ^[44][64] and their effect on slowing ADPKD progression, hoping for results that will allow for an increase in the number of therapeutic options for polycystic disease.