How Drug and Non-Drug Treatments Affect the Progression of Inherited Polycystic Kidney Disease

PKD1 and PKD2 code for two membrane proteins, polycystin-1 (PC1) and polycystin-2 (PC2), both associated with primary cilia. PC1 mediates cell–cell and cell–matrix interactions, acting as a receptor that regulates voltage-dependent calcium and potassium channels. Meanwhile, PC2 functions as a voltage-gated calcium channel. Together, these proteins form a complex on the primary cilia, playing a vital role in controlling intracellular calcium levels [5]. The interaction between PC1 and PC2 forms a complex on primary cilia responsible for the intracellular regulation of calcium levels [5]. PC1 is responsible for the mechanosensory function of primary cilia, cell adhesion and proliferation, and epithelial cell differentiation. Consequently, it is responsible for signaling affecting the processes of cellular growth and organization. PC2 plays a role in the regulation of calcium homeostasis in renal cells, specifically within the cell membrane and endoplasmic reticulum [6]. PC2 calcium channel dysfunction has been demonstrated to result in calcium homeostasis disorders, which in turn affect both apoptosis (programmed cell death) and cell proliferation. This, in turn, contributes to the development of cysts [7].

Figure 1 illustrates the interconnected pathological mechanisms underlying PKD, highlighting the fundamental concepts and the complex nature of the disease. Due to space constraints, we are unable to provide a comprehensive overview of the extensive PKD research. For a more in-depth exploration, readers are encouraged to consult the latest articles published by Dr. Albert Ong [2] and Dr. Jacob Torres [8].

Given the slow progression of the disease, various dietary strategies (including interventions in gut microbiome composition) and pharmacological approaches that may affect the progression of ADPKD should be considered. It is therefore recommended that treatment should include control of proteinuria, hypertension and elimination of smoking [9,10], adherence to a low-protein diet and dietary recommendations resulting from accompanying units, monitoring, and treatment of complications related to cysts and kidney stones, as well as treatment of urinary tract infections that may occur as a result of infection and dysbiosis [11]. Additionally, pain management should be considered [12,13].

In the case of ADKPD patients, appropriate supplementation can support the health of patients, although it is not clear what changes in the microbiota composition result from kidney failure itself and which are due to medications, diet, and comorbidities. In one study, changes in the gut bacterial microbiota in patients with ADPKD at various stages of CKD were first presented [14]. Dietary interventions such as ketogenic diet, calorie restriction, and intermittent fasting are potential strategies for inducing metabolic reprogramming and slowing ADPKD progression [15]. It is worth noting that other studies have previously provided important results regarding dietary interventions in ADPKD. Specifically, Nowak [16] conducted a study comparing intermittent fasting and calorie restriction in obese patients with ADPKD. They found a correlation between slowed kidney growth and weight loss, regardless of the diet regimen [17]. This information is of great significance, as it highlights the necessity of maintaining a healthy body weight as the fundamental principle of dietary practice. A ketogenic diet, calorie restriction, intermittent fasting, and time-restricted feeding can reduce aerobic glycolysis and inhibit the mTOR pathway, resulting in decreased cyst cell proliferation, reduced kidney volume, and preservation of kidney function. mTOR signaling has been identified as a pivotal pathway regulating renal epithelial cells from the glomerular bundle to the terminal segment of the nephron. Both mTOR complexes, mTORC1 and mTORC2, have been demonstrated to regulate a number of processes, including glomerular filtration and the fine-tuning of tubular electrolyte balance. In the context of obstruction resulting from dysfunction of calcium and/or potassium channels, a reduction in cell proliferation may be a significant factor [18]. However, it is not a dietary element that directly affects the cause of the disease, so other modifications may contribute to achieving greater benefits for the patient. A balanced diet is recommended for individuals with ADPKD, with particular attention paid to maintaining optimal blood pressure, adequate hydration, moderate protein intake, and controlled levels of phosphorus and potassium. Additionally, the consumption of healthy fats, such as monounsaturated and polyunsaturated fats (MUFA, PUFA), and fiber is encouraged [10]. Increased fluid intake may be recommended during the early stages of the disease but should be avoided in patients with moderate to severe renal impairment. [19]. Regular consultation with a dietitian is essential for individuals with ADPKD to ensure their dietary needs and health status are met.

A key issue, especially in temperate and subarctic climates, is vitamin D supplementation, which should be monitored by a physician to avoid excessive calcium levels [20]. Vitamin D has renoprotective effects, potentially reducing blood pressure and inflammation. Moreover, low serum 25(OH)D levels and vitamin D receptor (VDR) expression are associated with larger kidney volume in patients with ADPKD [20]. Vitamin D deficiency is associated with proteinuria and higher mortality and may contribute to kidney dysfunction [21]. However, studies on vitamin D supplementation in this group of patients have not been conducted. The clinical benefits of supplementation with curcumin, ginkgolide B, saponins, vitamin E, or triptolide in patients with ADPKD remain uncertain. The combination of curcumin and ginkgolide B has been demonstrated to exert a synergistic inhibitory effect on cystogenesis. The anti-cystogenic effects of curcumin were found to be mediated by the blockade of the epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinases (JNK), and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathways. In contrast, ginkgolide B was observed to inhibit cystogenesis by reducing the expression of EGFR/ERK1/2, JNK, and p38 signaling pathways [22]. Conversely, curcumin supplementation did not enhance blood vessel function or decelerate kidney growth in pediatric and young adult patients with ADPKD [23]. One study indicates Saikosaponin-d (SSd), an inhibitor of the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) pump, as a possible therapeutic target [24]. Notably, β-hydroxybutyrate supplements have shown promise in animal models; however, their safety and efficacy in ADPKD require further evaluation through well-designed clinical trials [25]. In addition to single-treatment studies targeting metabolic reprogramming in ADPKD, there is strong potential to combine these therapies with compounds that target other altered signaling pathways, such as vasopressin receptor antagonists. Pharmacological treatment trials also include the use of AMP-activated kinase activators (AMPK), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), niacinamide, thiazolidinediones, GLP-1 agonists, and mTOR inhibitors (mammalian target of rapamycin). AMPK is highly expressed in the kidney and regulates a number of physiological processes. It participates in carbohydrate and lipid metabolism, regulation of cell cycle and mitochondrial energetics, and inhibits inflammation and fibrosis [26]. Renal cystic tissues exhibit a metabolic reprogramming profile that mimics the "Warburg effect" of proliferative tissues (aerobic glycolysis) [26]. Furthermore, AMPK regulates cell growth by inhibiting the serine-threonine protein kinase mTORC. Song et al. suggest that metformin is an indirect activator of AMPK with a very good safety profile—both features making it an attractive candidate for the treatment of ADPKD [27]. Salsalate was also effective in ameliorating the severity of cystic disease by reducing the incidence of renal failure (BUN > 20 mmol/l), KW/BW. Salsalate treatment was associated with reduced mTORC1 activity and cell proliferation [27].

The effects of herbs and natural supplements on ADPKD patients can be unpredictable, particularly in cases where they affect kidney function. It is imperative that patients consult with a qualified medical professional prior to initiating any herbal or natural supplement regimen. There is a paucity of studies in the scientific literature on this topic. A number of studies have been conducted on this topic, but none have included a follow-up phase [28]. It appears that herbs with diuretic properties may assist in the elimination of excess fluids and toxins from the body. Such herbs include nettle, dandelion, parsley, and cranberries, which possess antibacterial properties. It is not advisable to consume licorice, as it has been linked to sodium and water retention, which can contribute to the development of hypertension [29]. Furthermore, fenugreek is contraindicated because of its potential to elevate potassium levels, particularly in individuals with the PKD1 mutation. However, the excessive intake of silica can result in an increased burden on the kidneys and disturbances in electrolyte balance [30]. It is therefore recommended that herbs containing significant amounts of silica, such as horsetail, bamboo, green oats, and, for the same reasons, nettle and dandelion, should be used with caution. At present, no studies have been conducted in this area. However, this is the opinion recommended by the authors of this review.

To determine the quality and quantity of physical activity that patients can safely perform, it is necessary to thoroughly assess the multisystemic nature of the disease, especially the involvement of the cardiovascular system [25].

Patients with ADPKD tend to experience an increase in body mass index (BMI) over time, mirroring trends in the general population [52]. About two-thirds of adults with ADPKD are classified as overweight or obese, which is a recognized risk factor for chronic kidney disease and end-stage renal disease. Weight loss has been shown to slow the decline in kidney function [53,54,55]. Recent research, such as the HALT-PKD study (in which 441 patients were observed for 5 years), has revealed that being overweight or obese significantly accelerates kidney growth in ADPKD, with obese individuals experiencing a faster decline in kidney function [53]. Excessive food intake and obesity activate the mTOR (mechanistic target of rapamycin) pathway through the PI3K/Akt and IGF-I signaling pathways, along with AMPK [56]. Notably, overstimulation of mTOR has been linked to the onset of diabetes [57]. Reduced AMPK activity observed in obese rodent models suggests that AMPK activation could offer a promising therapeutic strategy for PKD [58]. This points to a potential connection between higher body mass index (BMI) and PKD, indicating that increased BMI might contribute to the progression of PKD or that PKD itself could promote obesity.

Several dietary approaches have shown promise in slowing ADPKD progression. These include daily calorie restriction, intermittent fasting (fasting or significantly reducing caloric intake for 1–3 days per week), time-restricted feeding (limiting food intake to a specific window each day), and altering macronutrient composition, such as adopting low-fat, low-protein, or low-carbohydrate diets.

Dietary interventions aimed at metabolic pathways have been extensively explored in rodent models without PKD. Sustained calorie restriction, combined with sufficient nutrition, has been shown to prolong lifespan in many animal studies and improve key health metrics related to aging, such as body weight, lipid levels, and glucose regulation [59]. Additionally, calorie restriction has been found to offer protection against ischemia-reperfusion kidney injury in rodents, likely through mechanisms such as enhanced autophagy and greater stress resistance or preconditioning [60].

Intermittent fasting has also yielded several positive effects in non-PKD rodent models, including lower fasting glucose and insulin levels, better insulin sensitivity, improved lipid profiles, and reductions in both blood pressure and heart rate. It has been shown to mobilize glycogen and fat stores, leading to increased production of ketone bodies and gluconeogenesis, which could result in a shift from carbohydrate to fat metabolism [61].

In a prominent study on Drosophila [62], time-restricted feeding was shown to slow the aging of the heart, improve sleep quality, and prevent weight gain, all without changes to total calorie intake or activity levels. Similarly, in rodents, time-restricted feeding helped prevent weight gain from high-fat, high-sucrose diets and improved overall body composition [63,64]. This approach also enhanced insulin sensitivity, similar to intermittent fasting. In mice fed a high-fat diet, time-restricted feeding improved mTOR and AMPK signaling when compared with those fed without restriction [64].

Most clinical trials on calorie restriction have been conducted on healthy populations, focusing on weight loss and insulin sensitivity rather than disease-specific outcomes. However, the CALERIE trial, which involved 220 healthy volunteers over two years, demonstrated that a 25% reduction in daily caloric intake was feasible, safe, and led to improvements in reductions in inflammatory markers, cardiometabolic risk factors, despite some concerns about bone loss and anemia [65].

Research on intermittent fasting in healthy, overweight, and obese adults has demonstrated that it is both practical and safe [66,67,68]. Beyond aiding in weight and fat reduction, intermittent fasting has been linked to decreased oxidative stress, lower inflammation, reduced blood pressure, and improved lipid levels.

A newer approach, time-restricted feeding (TRF), offers an alternative method for weight management, particularly for those with a normal BMI, and may be more sustainable than intermittent fasting. TRF leverages similar evolutionary mechanisms, illustrating how the timing of meals can significantly impact metabolic processes [69]. Although randomized controlled trials (RCTs) on TRF are fewer compared with intermittent fasting, one 16-week pilot study in overweight individuals found that reducing daily caloric intake by 20% led to moderate weight loss, improved energy levels, and better sleep, with these effects lasting up to a year [69].

Moderate daily calorie restriction (ranging from 10–40%) has been shown to significantly slow kidney enlargement and enhance kidney function in animal models of ADPKD [33,70]. This effect is partly due to the suppression of mTOR signaling, activation of AMPK, and a reduction in IGF-I levels [70]. Moreover, calorie restriction reverses the ADPKD-related increase in hexokinase 2 expression, a key enzyme in glycolysis, promoting metabolic reprogramming [33]. Improvements in kidney fibrosis, inflammation, and damage markers have also been observed in a dose-dependent manner. Notably, a 40% calorie reduction, even when initiated in the later stages of the disease, not only slows ADPKD progression but can also reverse it [33]. Time-restricted feeding has also shown promising results in the Han:SPRD rodent model of PKD [71]. When rodents were allowed ad libitum feeding within an 8-h window during their active phase, significant reductions in cyst formation, kidney fibrosis, and improved kidney function were observed, along with the normalization of mTORC1 and STAT3 signaling—all without altering total calorie intake or body weight. Similar benefits were seen with a ketogenic diet or supplementation with the natural ketone β-hydroxybutyrate, which promotes metabolic reprogramming by shifting fuel sources, lowering glucose availability, and increasing fatty acid oxidation [8].

Additionally, protein restriction has been beneficial in improving PKD outcomes in two rodent models [72], while a soy-based diet has been shown to halt PKD progression by modifying lipid metabolism [73]. Reducing lipid intake has also been found to impact cyst growth in these models [31].

Tolvaptan, a highly selective V2 vasopressin receptor (AVP) antagonist, is the only approved therapy specifically for treating ADPKD. Research demonstrates that Tolvaptan slows the progression of cyst growth and curbs the increase in total kidney volume (TKV), effectively delaying the onset of end-stage kidney disease (ESKD). Normally, AVP binds to V2 receptors in the distal nephron and collecting ducts, stimulating the production of cAMP, which drives cyst formation. Tolvaptan works by blocking this AVP binding, leading to aquaresis (water excretion without sodium loss), reduced urinary osmolality, and a decrease in cyst proliferation by inhibiting cAMP production. Currently, Tolvaptan is recommended for ADPKD patients who are at high risk of rapid disease progression [74].

Nowadays, therapy with tolvaptan should be recommended to all ADPKD patients with probable rapid progression of the disease. Criteria for tolvaptan use are proposed as follows: 1. age 18–55 years, 2. chronic kidney disease CKD 1–4 (eGFR ≥ 25 mL/min per 1.73 m²), 3. high risk measured by available risk scores (longitudinal diameter > 17 cm by ultrasound, total kidney volume > 750 mL, Mayo imaging classification 1C, 1D, 1E or PROPKD score > 6), and 4. rapid decline of eGFR 3 mL/min per > 1.73 m²) for 5 years.

The Mayo imaging classification, developed from MRI data, is a reliable predictor of eGFR decline based on initial kidney volume [75]. Similarly, the PROPKD score estimates disease prognosis by integrating genetic information with clinical factors such as sex, age at onset of hypertension, age at first occurrence of macroscopic hematuria, and cyst-related flank pain [76]. Risk stratification is crucial, as individuals with a low likelihood of ADPKD progression tend to experience no significant decline in eGFR [77]. Therefore, Tolvaptan is not recommended for patients with ADPKD who are anticipated to have a mild disease trajectory.

Metformin, an FDA-approved activator of the AMPK pathway, is widely used for treating type 2 diabetes and polycystic ovary syndrome. Research involving kidney epithelial cell cultures and PKD mouse models has shown that metformin inhibits mTOR signaling and the cystic fibrosis transmembrane conductance regulator (CFTR), reducing epithelial proliferation and secretion, thereby slowing cyst growth [78,79]. Similarly, other studies on animal models have demonstrated that statins, also AMPK activators, can minimize cyst formation, preserve kidney function, and reduce gut inflammation and fibrosis [80]. Currently, two prospective randomized controlled trials (RCTs) are underway to investigate metformin as a potential treatment for ADPKD. The first, titled "Trial for Administration of Metformin to Tame PKD" (NCT0256017), is a phase II, double-blind, placebo-controlled RCT. It spans 26 months and includes 96 non-diabetic adults aged 18–60 with ADPKD and eGFR greater than 50 mL/min per 1.73 m². The study's primary objectives are to evaluate the safety and tolerability of metformin, while secondary measures focus on changes in total kidney volume (TKV), liver volume, pain, quality of life, and biomarkers related to the glycolytic and AMPK pathways. The second RCT (NCT02903511) involves 50 non-diabetic adults aged 30–60 years with ADPKD and an eGFR of 50–80 mL/min per 1.73 m². This year-long study primarily evaluates the proportion of participants who are able to take the full or at least 50% of the prescribed dose after 12 months. Secondary endpoints include changes in TKV and eGFR. Additionally, a direct comparison trial between metformin and tolvaptan is planned in Italy (NCT03764605) for 2020, involving 150 adults aged 18–50 years with eGFR ≥ 45 mL/min per 1.73 m² and a PKD1 mutation. However, this study has yet to commence. Statins, another AMPK activator approved by the FDA, have been shown to slow kidney growth in a three-year RCT involving children and young adults with ADPKD [81]. An ongoing RCT in which 150 pts, 40 mg of pravastatin, or placebo are participating is evaluating whether a 2-year pravastatin treatment provides similar benefits in TKV change in adults with ADPKD and preserved kidney function (NCT03273413).

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are relatively newer drugs that lower blood sugar by increasing glucose excretion in urine. In a rat model (Han:SPRD) of polycystic kidney disease (PKD), phlorizin, an SGLT1/2 inhibitor, reduced cyst formation after five weeks of treatment [82]. However, the SGLT2 inhibitor dapagliflozin improved kidney function and reduced albuminuria but did not stop cyst growth [83] and even increased cyst size in a different rat model of autosomal dominant polycystic kidney disease (ADPKD) [84]. Similarly, canagliflozin showed no benefit in reducing kidney disease severity in an ADPKD model [85]. Yet, in a study of 4401 patients with type 2 diabetes and chronic kidney disease (CKD), canagliflozin (100 mg) lowered the risk of kidney failure and cardiovascular events, prompting early trial termination [86].

Caution is recommended when considering SGLT2 inhibitors for ADPKD treatment.

Niacinamide (nicotinamide), a form of niacin, inhibits the NAD-dependent enzyme SIRT-1, which acts as a metabolic sensor. SIRT-1 expression is elevated in the kidneys of several polycystic kidney disease (PKD) rodent models [84]. Niacinamide has been shown to slow cyst growth and improve kidney function in two mouse models of autosomal dominant polycystic kidney disease (ADPKD), likely through SIRT-1 inhibition [87]. Interestingly, while calorie restriction activates SIRT-1 [59], it doesn't seem to affect SIRT-1 levels in PKD kidneys [33]. A phase II trial (NCT02558595) is evaluating niacinamide in ADPKD patients over one year. Early trials (N = 10 and N = 36) tested niacinamide's biological activity and safety, with primary outcomes focused on changes in SIRT-1-mediated p53 acetylation. Other measures include adjusted total kidney volume, eGFR, and monocyte chemoattractant protein-1.

Thiazolidinediones, FDA-approved drugs for managing high blood glucose in type 2 diabetes, activate PPARγ, a regulator of fatty acid and glucose metabolism. They also inhibit cystic fibrosis transmembrane conductance regulator activity and chloride secretion in response to vasopressin [88]. Pioglitazone and rosiglitazone have been effective in reducing cyst formation in several animal models of polycystic kidney disease (PKD) [89,90]. A 1-year phase II crossover study is currently evaluating the safety and efficacy of pioglitazone in non-diabetic adults with autosomal dominant polycystic kidney disease (ADPKD), with safety as the primary focus and total kidney volume (TKV) as a secondary endpoint (NCT02697617). However, the FDA has issued a warning about a potential increased risk of bladder cancer with pioglitazone, urging caution.

GLP-1 analogs, which have an established role in the treatment of type 2 diabetes and obesity, can also be used in the treatment of individuals with liver and kidney complications [91,92,93]. One of the appealing aspects of the new generation of GLP-1 analogs is the significant weight reduction (>10%) achieved in obese and diabetic patients [94]. Importantly, GLP-1 exerts its effects by binding to the GLP-1R receptor and activating adenylate cyclase, leading to an increase in cAMP production. Therefore, it is necessary to investigate the expression of GLP-1R in cyst epithelium and the potential impact of GLP-1 agonism on cAMP levels [91,95].

In humans with ADPKD, the mTOR inhibitors rapamycin and everolimus have demonstrated no clear-cut benefit. After 2 years of everolimus/placebo treatment in 433 patients (2 × 2.5 mg or placebo), increasing TKV slowed transiently but renal function worsened [103]; 18 months of rapamycin therapy in 100 patients receiving rapamycin (2 mg daily) or standard of care had no effect on TKV but was associated with a trend toward slowing of renal function decline [104]; and 6 months of rapamycin treatment had no protective effect on renal function or TKV but was associated with a decrease in the relative change and a trend toward an absolute change in renal cystic volume [105]. Currently, it appears that research on the use of mTOR in ADPKD, despite a solid theoretical foundation and a proven mechanism of action, has not demonstrated sufficient effectiveness in limiting cyst growth and will not be continued because of the emergence of better therapeutic options.