Comprehensive Review of Polycystic Kidney Disease and Herbal Ingredients for its Management

Polycystic kidney disease (PKD) is a genetically inherited disorder characterized by the progressive formation of multiple cysts in the renal parenchyma, leading to enlarged kidneys, impaired renal function, and, eventually, end-stage renal disease (ESRD). PKD is a significant contributor to chronic kidney disease (CKD) worldwide, affecting approximately 1 in 500 to 1,000 individuals, with autosomal dominant PKD (ADPKD) accounting for the vast majority of cases, and autosomal recessive PKD (ARPKD) occurring less frequently but with more severe early-onset symptoms. [1] The pathogenesis of PKD is complex and multifactorial, involving genetic mutations (notably in PKD1 and PKD2 genes), disrupted calcium signaling, increased cell proliferation, abnormal fluid secretion, and chronic inflammation. As cysts grow, they compress surrounding nephrons, gradually reducing kidney function and contributing to complications such as hypertension, hematuria, urinary tract infections, and kidney stones. Although pharmacological interventions such as vasopressin V2 receptor antagonists (e.g., tolvaptan)—have shown some success in slowing cyst progression, their efficacy is limited and they are often associated with adverse effects and high costs. As a result, there is growing interest in alternative and complementary therapies, particularly herbal and plant-based compounds, which have demonstrated promising anti-inflammatory, antioxidant, and anti-fibrotic properties in preclinical models. [3] Herbal medicine, an integral component of traditional medical systems such as Ayurveda, Traditional Chinese Medicine (TCM), and Unani, offers a wide array of bioactive compounds that may modulate the molecular pathways involved in PKD progression. Notably, phytochemicals such as curcumin, resveratrol, cordycepin, and salvianolic acid B have been investigated for their potential to reduce cyst growth, oxidative damage, and renal fibrosis. This review aims to provide a comprehensive examination of the current understanding of PKD, including its molecular mechanisms, clinical manifestations, and conventional treatments, while exploring the therapeutic potential of herbal ingredients for its management. By synthesizing evidence from experimental and clinical studies, we aim to highlight promising natural compounds and identify gaps in research that warrant further investigation. [2]

Figure 1: Polycystic kidney

Overview of Polycystic Kidney Disease (PKD)

Polycystic Kidney Disease (PKD) is a genetic disorder characterized by the development and progressive enlargement of multiple fluid-filled cysts within the kidneys. These cysts arise from various segments of the renal tubules and eventually disrupt normal renal architecture and function, often leading to chronic kidney disease (CKD) and ultimately end-stage renal disease (ESRD). PKD is one of the most common inherited kidney disorders, and it exists in two primary forms:

1. Autosomal Dominant Polycystic Kidney Disease (ADPKD) [5]

• Prevalence: Affects ~1 in 400 to 1,000 live births.
• Inheritance: Autosomal dominant (only one mutated allele is required for disease manifestation).
• Genetics:
  • Caused primarily by mutations in the PKD1 gene (chromosome 16) encoding polycystin-1, and less commonly in PKD2 (chromosome 4) encoding polycystin-2.
  • PKD1 mutations tend to result in more severe disease progression.
• Clinical Onset: Typically presents in adulthood, but cysts begin forming much earlier. [7]
• Common Symptoms:
  • Hypertension
  • Flank pain
  • Hematuria
  • Recurrent urinary tract infections (UTIs)
  • Progressive renal enlargement
• Extra-renal Manifestations:
  • Hepatic cysts
  • Intracranial aneurysms
  • Cardiac valve abnormalities (e.g., mitral valve prolapse)
  • Colonic diverticulosis [11]

2. Autosomal Recessive Polycystic Kidney Disease (ARPKD)

• Prevalence: Much rarer (~1 in 20,000 live births).
• Inheritance: Autosomal recessive (both alleles must be mutated).
• Genetics: Caused by mutations in the PKHD1 gene, which encodes fibrocystin/polyductin.
• Clinical Onset: Presents in infancy or early childhood.
• Features:
  • Enlarged echogenic kidneys detected prenatally
  • Pulmonary hypoplasia due to oligohydramnios
  • Portal hypertension from hepatic fibrosis
  • High perinatal mortality [13]

Pathophysiology of PKD

PKD involves dysregulation of tubular epithelial cell proliferation, fluid secretion, apoptosis, and extracellular matrix remodeling. Mutations in polycystin or fibrocystin disrupt calcium signaling, ciliary function, and mTOR pathways, which are critical in maintaining the structural integrity and polarity of renal tubular cells. These disruptions lead to abnormal cyst formation and progressive kidney enlargement. [15]

Disease Progression and Complications

• In ADPKD, renal function typically remains stable until the 4th or 5th decade, after which there is a rapid decline toward ESRD.
• Complications include:
  • Renal insufficiency
  • Kidney stones
  • Cyst rupture and hemorrhage
  • Cardiovascular complications (due to hypertension)
  • Increased risk of infections (especially cyst infections)

Current Management Strategies

While no cure exists, disease-modifying strategies aim to delay progression and manage complications: [17]

• Tolvaptan, a vasopressin V2 receptor antagonist, is the only FDA- and EMA-approved drug to slow cyst growth in ADPKD.
• Supportive therapy includes:
  • Blood pressure control (ACE inhibitors or ARBs)
  • Pain management
  • Infection control
  • Dietary modifications
  • Dialysis or renal transplantation in ESRD

Herbal and Natural Approaches in PKD Management

The management of Polycystic Kidney Disease (PKD) has traditionally focused on supportive care and, more recently, disease-modifying agents like tolvaptan. However, limitations such as side effects, cost, and incomplete efficacy have spurred interest in herbal and natural therapies. Medicinal plants and their bioactive compounds offer a promising adjunctive approach due to their anti-inflammatory, antioxidant, anti-fibrotic, and cytostatic properties, which may target several pathophysiological mechanisms of cyst growth and renal damage.[12]

1. Mechanistic Rationale for Herbal Use in PKD

Herbal therapies can influence PKD progression through:

• Inhibition of cyst epithelial proliferation
• Suppression of oxidative stress
• Modulation of inflammatory pathways
• Regulation of fibrogenesis
• Inhibition of mTOR and cAMP signaling, both implicated in cyst growth

Many plant-derived compounds have been shown to interact with these pathways in preclinical models of PKD.

2. Key Herbal Ingredients and Their Therapeutic Potential [14]

a. Curcumin (Curcuma longa)

• Actions: Antioxidant, anti-inflammatory and anti-fibrotic
• Mechanisms:
  • Inhibits NF-κB and TGF-β signaling
  • Reduces cyst formation in animal models of PKD
• Evidence:
  • Curcumin treatment in murine models of ADPKD has shown reduced cystic burden and improved renal function.

Figure 2: Curcumin

b. Resveratrol

• Source: Found in grapes, berries, and peanuts
• Actions: Sirtuin activation, antioxidant, anti-inflammatory
• Mechanisms:
  • Activates SIRT1, suppressing mTOR signaling
  • Reduces oxidative stress in kidney tissues [18].
• Evidence:
  • Shown to decrease renal fibrosis and delay cyst progression in rodent studies.

c. Astragalus membranaceus

• Used in: Traditional Chinese Medicine (TCM)
• Actions: Immunomodulatory, diuretic, anti-inflammatory
• Mechanisms:
  • Reduces serum creatinine and BUN levels
  • Inhibits renal interstitial fibrosis
• Evidence:
  • Used in Chinese herbal prescriptions for CKD and PKD, often in combination with other herbs. [13]

Figure 3: Astragalus Membranaceus

d. Cordyceps sinensis

• Actions: Antioxidant, immunomodulatory, anti-fibrotic
• Mechanisms:
  • Modulates AMPK and TGF-β1 signaling

Figure 4: Cordyceps sinensis

• Evidence:
  • Clinical studies in CKD show improved renal function markers and decreased proteinuria. Figure (4).                                                  

e. Salvia miltiorrhiza (Danshen)

• Actions: Anti-fibrotic, vasodilatory, anti-inflammatory
• Mechanisms:

Figure 5: Salvia Miltiorrhiza (Danshen)

• • Inhibits TGF-β1/Smad pathway
  • Improves renal microcirculation
• Evidence:
  • Demonstrated renal protective effects in diabetic nephropathy and PKD-related studies. Fig (5)

f. Tripterygium wilfordii (Thunder God Vine)

• Actions: Immunosuppressive, anti-inflammatory
• Mechanisms:
  • Inhibits pro-inflammatory cytokines and immune cell activation
• Cautions:
  • Potent but potentially toxic; use requires careful dosing and monitoring. [14]

Figure 6: Tripterygium wilfordii (Thunder God Vine)

3. Dietary and Nutraceutical Compounds

Some natural dietary compounds and plant extracts have also shown promise in PKD models: Table 1: Dietary and Nutraceutical Compounds

4. Challenges and Considerations

While herbal remedies show potential, several challenges must be addressed:

• Lack of standardized dosages and formulations
• Insufficient clinical trials specifically for PKD
• Potential for herb–drug interactions, especially in patients on immunosuppressants or diuretics
• Toxicity and quality control concerns with poorly regulated herbal products
• Variability in bioavailability and pharmacokinetics of plant compounds. [21]

5. Integrative Potential and Future Directions

• Combination therapies involving herbal extracts and conventional agents (e.g., tolvaptan + curcumin) may offer synergistic effects.
• Nano-formulations and encapsulation techniques are being explored to improve bioavailability.
• Clinical trials are needed to translate promising preclinical data into validated, evidence-based therapies. [23]

Preclinical and Clinical Evidence

The exploration of herbal and natural compounds for the treatment of Polycystic Kidney Disease (PKD) has expanded in recent years, driven by the need for safer, more accessible therapies with fewer side effects than current pharmacologic options. A growing body of preclinical studies supports the efficacy of various herbal agents in modulating key pathways involved in PKD pathogenesis, such as mTOR signaling, oxidative stress, inflammation, and fibrosis. However, clinical evidence remains limited, highlighting the need for well-designed trials. [13]

1. Preclinical (In-Vitro and In-Vivo) Evidence

Numerous animal models (e.g., Pkd1 or Pkd2 knockout mice, Han: SPRD rats) and renal epithelial cell lines have been used to evaluate herbal compounds mentioned below Table (2).

Table 2: Preclinical (In-Vitro and In-Vivo) Evidence

2. Clinical Evidence

Despite robust preclinical data, clinical trials evaluating herbal interventions specifically for PKD are limited. Most available studies assess herbal formulations in general chronic kidney disease (CKD) populations or as part of Traditional Chinese Medicine (TCM) therapies.

Notable Clinical Studies and Observations:

1. Cordyceps sinensis in CKD patients:
   • Several trials in China reported improvements in serum creatinine, albuminuria, and hemoglobin levels.
   • Some studies included PKD patients, but lacked subgroup analysis.
   • Generally well tolerated, though long-term safety remains under investigation.
2. Astragalus membranaceus:
   • Used in TCM formulations for CKD and PKD.
   • A randomized trial (Zhou et al., 2014) in CKD patients showed reduced proteinuria and improved renal function with Astragalus-based therapy. [16]
3. Curcumin in renal disease:
   • Small-scale studies in diabetic nephropathy showed reduced inflammation and oxidative markers.
   • No PKD-specific clinical trials yet, but evidence supports its safety and renal benefits.
4. TCM compound formulas:
   • Multi-herbal decoctions like Shen Qi Wan, Huangkui capsules, and Liuwei Dihuang Wan are used in China for PKD treatment.
   • Some observational studies report slowed cyst growth and improved quality of life, but high-quality RCTs are lacking. [14]
5. Safety Profile:
   • Most herbal agents are well-tolerated at recommended doses.
   • Concerns include:
     • Hepatotoxicity (e.g., from Tripterygium wilfordii)
     • Interaction with conventional drugs
     • Variability in product quality and standardization.

Limitations of Current Evidence

• Few herbal interventions have undergone phase II/III clinical trials for PKD.
• Many studies have:
  • Small sample sizes
  • Poor blinding or randomization
  • Use of multi-herb formulations, making it difficult to attribute effects to a single ingredient
• Lack of standardized herbal extracts and bioavailability data
• Endpoints often vary (e.g., cyst size vs. renal function vs. patient-reported outcomes)

Future Research Directions

To translate preclinical promise into clinical utility:

• Well-designed RCTs are needed with clearly defined inclusion criteria (e.g., confirmed ADPKD diagnosis).
• Biomarker-based endpoints (e.g., TKV, eGFR) should be included.
• Herbal pharmacokinetics and metabolism in CKD patients must be better understood.
• Combination therapy studies (herbal + conventional) could evaluate synergistic effects. [15]

Safety, Toxicity and Interactions

While herbal and natural compounds offer promising therapeutic potential in the management of Polycystic Kidney Disease (PKD), their use must be carefully evaluated for safety, potential toxicity, and interactions with conventional medications. Unlike regulated pharmaceuticals, many herbal products vary in composition, dosage, and purity, posing unique risks, especially in individuals with impaired renal function. [16]

1. General Safety Concerns in PKD Patients

Patients with PKD, particularly those in the later stages of chronic kidney disease (CKD), are more vulnerable to toxic effects due to:

• Impaired drug clearance, increasing the risk of accumulation and toxicity
• Altered metabolism of herbal compounds due to compromised renal or hepatic function
• Polypharmacy, heightening the potential for drug-herb interactions [17]

2. Toxicity of Commonly Used Herbal Ingredients:

Table 3: Herbal Ingredients

3. Herb–Drug Interactions

Many herbal compounds can alter the pharmacokinetics or pharmacodynamics of prescription drugs through:

Cytochrome P450 enzyme modulation

• Some herbs (e.g., St. John’s Wort, ginseng) induce or inhibit CYP enzymes, potentially altering metabolism of drugs like:
  • Tolvaptan (used in ADPKD)
  • ACE inhibitors/ARBs (used for hypertension)
  • Immunosuppressants (in post-transplant patients)

Pharmacodynamic interactions

• Herbs that lower blood pressure, blood sugar, or act as diuretics may amplify effects of prescribed medications, risking hypotension, hypoglycemia, or dehydration. [18] 

Examples of Known Interactions

Table 4: Examples of Known Interactions