Polycystic kidney disease (PKD) is a group of inherited disorders characterized by the formation of fluid-filled cysts in the kidneys, leading to progressive kidney enlargement and decline in function. PKD is broadly categorized into autosomal dominant PKD (ADPKD) and autosomal recessive PKD (ARPKD), with distinct genetic and clinical features.

ADPKD is the most common form of PKD, affecting millions worldwide (Rahbari-Oskoui et al., 2022). It is estimated that 1 in 400 to 1 in 1,000 individuals are affected with ADPKD, accounting for 5% - 10% of end-stage renal disease (ESRD) cases globally [6] [7] . The prevalence of ADPKD varies across different populations, with reported incidences ranging from 1 in 2,459 in the United Kingdom to 1 in 4,000 in some European and Japanese populations [7] . This variability may be attributed to factors such as genetic background, founder effects, and access to healthcare.

In the United States, ADPKD affects approximately 140,000 [8] . Interestingly, there is a gender difference in the age of diagnosis, with females often diagnosed earlier in adulthood due to increased abdominal imaging during pregnancy, while males tend to be diagnosed later, often after the onset of chronic kidney disease [8] .

ARPKD is a rarer form of PKD, affecting approximately 1 in 20,000 newborns [9] . Unlike ADPKD, which typically manifests in adulthood, ARPKD presents in childhood, often with severe and rapidly progressive kidney dysfunction. More than half of affected individuals develop ESRD by the age of 10, requiring dialysis or kidney transplantation for survival [10] .

In addition to kidney involvement, ARPKD is characterized by congenital hepatic fibrosis (CHF), a condition affecting the liver. Advances in medical care have led to increased recognition of the long-term effects of CHF, which can manifest at various stages of life, from infancy to young adulthood [11] .

Polycystic kidney disease (PKD) is characterized by the progressive development of fluid-filled cysts in the kidneys, leading to a wide range of clinical manifestations. While the presentation can vary based on the type and severity of PKD, some common symptoms include:

In addition to these primary symptoms, PKD can lead to complications like liver cysts, vascular aneurysms, and cardiovascular issues.

PKD is often considered a “silent” disease, as symptoms may not become apparent until later stages [15] . Early detection through imaging techniques like CT scans or MRI is crucial for managing symptoms and slowing disease progression. Incidental diagnoses are common during evaluations for unrelated conditions like pregnancy, back pain, or accidents [6] .

Several factors can accelerate the progression of PKD, including hypertension, proteinuria, kidney stone formation, gross hematuria, and specific genetic mutations like the PKD1 mutation [6] . In autosomal dominant PKD (ADPKD), parental evaluation is essential due to the hereditary nature of the disease.

Autosomal recessive PKD (ARPKD) often presents in the neonatal period with a range of symptoms, including abdominal swelling, respiratory distress due to underdeveloped lungs, decreased kidney function, hypertension, enlarged liver, jaundice, and poor growth [16] . Severe cases can lead to life-threatening complications like respiratory distress syndrome and renal failure, emphasizing the importance of early diagnosis and prompt treatment [17] . Table 2 shows the clinical manifestations of PKD.

ADPKD, the most prevalent form of PKD, arises from genetic alterations on chromosomes 16 and 4. Specifically, mutations in the PKD1 and PKD2 genes, encoding polycystin-1 and polycystin-2 proteins respectively, are implicated in the disease pathogenesis [18] . The PKD1 gene resides on chromosome 16p13.3, while PKD2 is located on chromosome 4q21.2 [19] . Notably, mutations in PKD1 account for approximately 85% of ADPKD cases, with the remaining 15% attributed to PKD2 mutations [20] .

ADPKD follows an autosomal dominant inheritance pattern, meaning an individual has a 50% chance of inheriting the mutated gene from an affected parent. Inheriting a single copy of the altered gene is sufficient to cause the disease [21] . Although the genetic defect is present from birth, the onset of symptoms can vary, with some individuals remaining asymptomatic until middle age or later.

ARPKD, also recognized as ciliopathy-associated polycystic kidney disease, is a less common form of PKD. It results from mutations in the PKHD1 gene on chromosome 6, which encodes fibrocystin, a protein crucial for the structure and function of primary cilia [22] .

Unlike ADPKD, ARPKD follows an autosomal recessive inheritance pattern. This implies that an individual must inherit two copies of the mutated PKHD1 gene, one from each parent, to develop the disease [16] . Consequently, ARPKD is less prevalent than ADPKD. The clinical presentation of ARPKD can manifest in newborns, children, or adults [11] .

Mutations in PKD1 or PKD2 disrupt the normal function of these proteins, leading to abnormal ciliary signaling and intracellular calcium dysregulation. This disruption triggers a cascade of cellular events, including increased fluid secretion, cell proliferation, and extracellular matrix remodeling, ultimately resulting in cyst formation [23] [24] .

Once initiated, cysts progressively enlarge due to fluid accumulation and cell proliferation, driven by various signaling pathways, including cAMP and mTOR. This expansion compresses surrounding renal tissue, leading to ischemia, inflammation, and fibrosis, further contributing to kidney damage [25] . However, this fibrosis contributes to additional kidney damage, eventually leading to chronic kidney disease (CKD) and end-stage renal disease (ESRD).

Beyond the kidneys, ADPKD can manifest in other organs, notably the cardiovascular system. Ciliary dysfunction in vascular smooth muscle cells is implicated in the development of aneurysms and hypertension, significant contributors to cardiovascular morbidity and mortality in ADPKD patients. Understanding the links between renal cystogenesis and these extrarenal manifestations, particularly those affecting the heart, is crucial for developing comprehensive management strategies for ADPKD.

An important hypothesis proposed to explain the development of cysts in PKD is the two-hit hypothesis. According to the two-hit hypothesis, the progress of cysts in the kidneys and other body parts or organs requires two separate genetic mutations, or “hits,” to occur [20] . The first hit involves an inherited metamorphosis in one of the PKD genes, PKD1 or PKD2. This initial genetic insult leads to the formation of small cysts in the kidneys, which are typically benign and asymptomatic early in life. However, these cysts can grow and expand with time, leading to the expansion of larger cysts and eventual kidney failure. The second hit in the two-hit hypothesis involves a somatic mutation in one of the residual PKD alleles within a cystic epithelial cell [26] .

Various experimental and clinical studies have supported the two-hit hypothesis. For example, patients with ADPKD caused by PKD1 mutations tend to have a more severe disease phenotype and an earlier onset of symptoms than those with PKD2 mutations. This difference may be explained by the fact that PKD1 encodes a more significant protein with more functional domains and is involved in more cellular processes than PKD2 [26] [27] . Therefore, a mutation in PKD1 may have a greater impact on the overall function and may require fewer additional hits to cause cyst formation.

Furthermore, studies have shown that cystic epithelial cells in ADPKD patients exhibit a “second-hit” mutation in the remaining PKD allele, suggesting that this process is necessary for cyst development [28] . Animal models of PKD have also reinforced this idea, which has shown that cyst formation and kidney enlargement require mutations in both PKD1 and PKD2.

a) Tolvaptan: Tolvaptan has shown encouraging outcomes in clinical studies as a treatment option for ADPKD. It works by inhibiting the activity of vasopressin, a hormone that promotes cyst growth. In clinical studies, Tolvaptan’s efficacy in decelerating renal cyst growth has been demonstrated [20] . However, Tolvaptan has some side effects, such as thirst, increased urine output, and fatigue, and is not recommended for patients with advanced liver disease.

b) Sirolimus and Everolimus: Sirolimus and Everolimus are immunosuppressant drugs studied to treat PKD. These drugs work by inhibiting the activity of the mTOR signaling pathway, which is a critical part of cyst growth [19] . Clinical trials have shown that both drugs can reduce cyst growth in patients with PKD, but their long-term effects are still under investigation.

c) Metformin: Metformin is an oral medication commonly used to treat diabetes. It has also been studied as a potential therapy for PKD. Metformin obstructs the activity of the AMP-activated protein kinase (AMPK) pathway, which promotes cyst growth in PKD [33] [34] . Research has indicated that metformin can potentially decrease cyst growth and ameliorate kidney function in patients with PKD.

Other potential treatments for PKD, such as gene therapy and stem cell therapy, are still in the early stages of development. Lifestyle modifications, such as following a healthy diet and exercising regularly, can also help to manage the symptoms of PKD and slow the progression of the disease.

The use of gene therapy shows potential as a method of treating genetic conditions such as PKD. Gene therapy aims to restore normal gene function by delivering a functional version of the mutated gene to affected cells. Several approaches have been developed for gene therapy in PKD, including:

a) Antisense Oligonucleotides (ASOs): ASOs are small molecules that can bind to specific RNA molecules and alter their function. In the case of PKD, ASOs can be designed to bind to RNA transcripts of the mutated gene and prevent them from being translated into the protein product [16] . This approach has been successful in preclinical studies and is currently being investigated in clinical trials.

b) CRISPR-Cas9: CRISPR-Cas9 is a powerful gene editing technology that can directly modify the target gene’s DNA sequence. In PKD, CRISPR-Cas9 can be used to correct the mutation in the PKD1 or PKD2 gene [20] . Although this approach is still in the early stages of development, it has shown promising results in preclinical studies.

c) Viral gene therapy: Viral gene therapy involves the use of a virus to deliver the functional gene copy to affected cells. Several types of viruses, including adeno-associated virus (AAV) and lentivirus, have been studied to treat PKD [20] . Although this approach has shown promise in preclinical studies, there are still concerns about the safety and efficacy of viral gene therapy.

Stem cell therapy is another promising approach for the treatment of PKD. Stem cells are a type of unspecialized cell that can differentiate into various cell lineages [35] . The successful generation of disease-specific induced pluripotent stem cells (iPSC) from kidney transplant patients provides a promising avenue for personalized therapy. iPSC-derived kidney cells have demonstrated the ability to reabsorb glucose and secrete renin, lower polycystin-two levels at the ciliary level indicating their potential for repairing and regenerating the kidneys [36] [37] .

The use of iPSC eliminates the risk of immune rejection, a significant challenge in the treatment of PKD patients with organ transplants. More studies are necessary to improve the iPSC generation process and evaluate the safety and efficacy of iPSC-based therapy for patients with PKD [36] . However, the generation of disease-specific iPSCs from kidney transplant recipients offers a potential solution to the difficulties of treating PKD and represents a promising direction for personalized regenerative medicine.

Patients with PKD can manage symptoms and reduce the progression of the disease by making diet and lifestyle modifications. Patients should follow a balanced diet that is low in sodium, protein, and fat. Sodium restriction is essential to control blood pressure, a significant risk factor for the progression of PKD [38] . Lowering protein intake can also slow the growth of cysts in the kidneys. In addition, excessive intake of caffeine and alcohol should be avoided and patients should quit smoking [22] . Regular exercise can also benefit PKD patients by controlling blood pressure and improving overall health

Hemodialysis and peritoneal dialysis are two distinct therapeutic modalities used to eliminate toxins and surplus fluids from the bloodstream when the renal system has lost its ability to carry out this vital function [39] .

a) Hemodialysis: Hemodialysis is a medical procedure that involves the use of a machine to remove waste products and excess fluids from the blood by filtering it outside the body. Vascular access is created, usually in an arteriovenous fistula, allowing blood to be withdrawn from the body and returned to the body after filtration [17] . The process typically takes 3-4 hours per session and is usually performed three times a week.

b) Peritoneal dialysis: Peritoneal dialysis is a type of dialysis that uses the peritoneum, which is a membrane that covers the abdominal cavity, to filter the blood. It involves the insertion of a catheter in the abdomen, followed by the infusion of a solution into the peritoneal cavity [19] . This solution remains in the peritoneal cavity for several hours, during which time it removes waste products and excess fluids. Then, the solution is drained from the body, and a new solution is infused.

A kidney transplant, including PKD, is considered the most efficient treatment for end-stage kidney disease. The procedure involves replacing damaged kidneys with a healthy kidney from a donor or a living or deceased donor [16] . Living donors are usually family members or close friends of the recipient and they undergo a thorough medical evaluation to ensure that they are healthy enough to donate a kidney. Deceased donors are individuals who have died and donated their organs for transplantation. After a kidney transplant, patients will need to take immunosuppressant drugs for the rest of their life to prevent rejection of the transplanted kidney [19] .

ESRD is a life-threatening disease and patients with ESRD have a higher mortality rate than the general population [46] . The fatality rate associated with end-stage renal disease in patients with PKD surpasses that observed in individuals diagnosed with other kidney pathologies. The mortality rate for patients with PKD with ESRD is approximately 14% per year, compared to approximately 8% per year for individuals with other forms of kidney disease [47] .

The increased mortality rate in PKD patients with ESRD is due to several factors. First, PKD patients with ESRD are more likely to have other comorbid conditions, such as hypertension, cardiovascular disease, and diabetes, which can further increase the risk of mortality. Second, patients with PKD with ESRD may be less likely to receive a kidney transplant than individuals with other types of renal disease due to the complex nature of the disease and the difficulty in finding suitable donors [46] .