Urolithiasis unveiled: pathophysiology, stone dynamics, types, and inhibitory mechanisms: a review

Abstract

Urolithiasis is a multifaceted and common urological disorder characterized by the development of renal calculi. Calcium oxalate stones are the most prevalent type of calculi, forming when calcium and oxalate combine to produce crystalline structures in the urine. The incidence rates of urolithiasis exhibit geographical variations, which are determined by factors such as geographic location, age, sex, dietary habits, and genetics. The increasing trend of urolithiasis has emerged as a noteworthy public health issue, potentially attributed to shifts in dietary and lifestyle habits. In response to this challenge, various inhibitors of calcium oxalate crystal formation, including small molecules, peptides, and proteins, have been developed. Moreover, substances such as citrate, magnesium, inter-alpha-trypsin inhibitors, phytate, potassium, and pyrophosphates show promise in preventing kidney stones. A comprehensive metabolic assessment is crucial, customized for each patient, to effectively manage and avoid the recurrence of urolithiasis. Although specific pharmacological treatments for urolithiasis are currently unavailable, some drugs can reduce pain. Some drugs, including calcium channel blockers like nifedipine, phosphodiesterase-5 inhibitors like tadalafil, and alpha-blockers like tamsulosin, are thought to lower ureteral contractions by making the ureteral smooth muscle relax. In acute and severe pain cases, intravenous administration of narcotic analgesics and anti-inflammatory agents may be employed in emergency medical settings. To enhance therapeutic approaches, it is essential to gain more knowledge about the pathophysiology of renal calculi. The development of inhibitors targeting calcium oxalate crystal formation offers a promising avenue for urolithiasis prophylaxis. Identifying and investigating potential inhibitors lays the framework for the creation of more effective and targeted therapeutic options.

Graphical Abstract

1 Background

Urolithiasis, derived from the Greek 'ouron' (urine), 'oros' (flow), and 'lithos' (stone), is a complex urological disorder characterized by the production of calculi in the kidneys, bladder, and urethra. Despite its longstanding prevalence in humans, urolithiasis poses significant medical and public health challenges [1]. The most common type of calculi in urolithiasis are calcium oxalate (CaOx) stones, which form when calcium combines with oxalate in the urine, resulting in crystalline structures. Other forms of calculi include uric acid, cystine, struvite, xanthine, ammonium acid urate, drug-induced stones, and dihydroxyadenine stones [2].

The geographical incidence of urolithiasis displays fluctuation, with generally greater rates in Western countries compared to the Eastern hemisphere. The incidence rates are approximately 1–5% in Asia, 5 to 9% in Europe, and 12% in Canada, with the USA reporting rates between 13 and 15%. A notably high incidence rate of 20.1% has been recorded in Saudi Arabia [3, 4]. Influencing factors include age and sex, with a larger prevalence in males compared to females [5], and the condition is most commonly observed in individuals in their thirties and forties [6]. The growing trend of urolithiasis over time is likely linked to changes in diet and lifestyle [7]. Since 1990, there has been a global increase in urolithiasis cases, disability-adjusted life years, and mortality rates [8]. In 2007, the estimated cost of treating urolithiasis in the United States was $3.79 billion, with forecasts showing a yearly increase of $1.24 billion by 2030 [9]. The chemical composition of organic components, such as phospholipids and albumin, contributes to the formation of CaOx and calcium phosphate calculi, influencing the development of various types of urolithiasis [10]. Factors affecting incidence rates include geographic location, climate, ethnicity, dietary habits, and genetics [11].

Managing urolithiasis requires comprehensive metabolic evaluation to prevent recurrence, with treatments tailored to individual patient needs [12]. While specific pharmacological treatments remain unavailable, some medications can alleviate pain. For instance, alpha-blockers like tamsulosin, particularly when combined with dutasteride, aid in the passage of calculi, reducing discomfort by relaxing the ureteral smooth muscles [13]. Calcium channel blockers such as nifedipine and phosphodiesterase-5 inhibitors like tadalafil are also effective in reducing ureteral contractions [14]. In severe cases, intravenous narcotic analgesics and anti-inflammatory agents are administered in emergency settings [14]. Developing inhibitors that target CaOx crystal formation is a promising approach to preventing urolithiasis. A comprehensive, multidisciplinary approach, integrating various treatment modalities, is essential for the successful management and prevention of urolithiasis recurrence.

2 Methodology of literature searching

We searched electronic databases including PubMed, ScienceDirect, and Scopus to gather information on the prevalence of urolithiasis, the different types of stones, inhibitors, and promoters. The search covered the period from 2000 to August 2023. Keywords used in the search were "kidney stone", "urolithiasis", "nephrolithiasis", "renal calculi", "renal stone", "kidney stone inhibitors", "kidney stone promoters", "kidney stone types", and "kidney stone formation mechanisms".

3 Pathophysiology of urolithiasis

Environmental and genetic variables both influence the complexity and multifaceted nature of urolithiasis. The development of urinary stones involves various mechanisms, and the formation of CaOx stones differs from that of other types of stones. Impaired renal acidification, along with altered renal excretion or excessive absorption in the digestive tract, leads to the accumulation of stone-forming metabolites [15].

Among the distinct pathomechanisms of CaOx stone formation, Randall plaques and mineral deposits, play a critical role [16, 17]. However, the emergence and pathophysiology of CaOx stones are still poorly understood, necessitating further research to identify effective prevention and treatment strategies. Recent studies suggest that the formation of interstitial apatite crystals may be an initial step in the development of CaOx stones [18].

Reduced urine volume raises the concentration of stone-causing compounds, which in turn promotes crystallization and stone formation, making urine volume a critical factor in the pathophysiology of urolithiasis [19]. Kidney stones are more likely to form when urine volume is reduced, which can happen as a result of dehydration, some drugs, or medical issues that impact fluid balance or urinary function. One of the most prevalent causes of kidney stones is not drinking enough water [20].

Certain medical conditions can increase the risk of developing kidney stones. Renal tubular acidosis is a condition in which the kidneys are unable to eliminate acids from the blood into the urine, leading to an increase in blood acidity. Other conditions, such as cystinuria, hyperparathyroidism, and recurring urinary tract infections, can also increase the chance of kidney stone formation [21, 22]. Further research is needed to fully comprehend the pathophysiology of these disorders and develop effective preventive and treatment strategies for urolithiasis.

4 Mechanism of stone formation

In individuals with risk factors for stone formation, such as high urinary supersaturation, low urinary volume, or low urinary pH, crystals may nucleate and aggregate into larger particles, potentially forming a stone. Stone formation can occur in various locations within the urinary tract, including the kidneys, ureters, bladder, and urethra. The development of stones can be influenced by several factors, including genetics, diet, lifestyle, and medical conditions such as urinary tract infections or metabolic disorders [18, 23].

Once a stone has formed, it can continue to grow with the addition of new crystals and may also move within the urinary tract, leading to pain and other symptoms. The ability of a stone to move through the urinary tract can be influenced by its size and chemical makeup. While larger stones may require medical intervention for removal, smaller stones are more likely to pass spontaneously [24, 25].

4.1 Urinary supersaturation

The initial stage of kidney stone formation is urinary supersaturation, which occurs when the concentration of certain substances in the urine, such as calcium, oxalate, and phosphate, exceeds their solubility limit. This leads to a state in which the urine becomes supersaturated, creating an environment conducive to the formation of crystals. Under these conditions, the excess solutes can no longer remain dissolved and begin to aggregate, resulting in the formation of small crystal particles [26]. These small particles can then combine and grow into larger crystals, eventually leading to the formation of kidney stones.

The degree of supersaturation, along with other factors such as urinary pH and the presence of inhibitors or promoters of crystal growth, can significantly influence the formation and growth of crystals, and ultimately the development of kidney stones. Understanding the factors contributing to urinary supersaturation and the subsequent crystal formation is important for the prevention and treatment of kidney stones [26, 27].

4.2 Crystallization

The process of crystallization occurs when urine becomes oversaturated, leading to the formation of solid crystals. The specific type and characteristics of the crystals depend on the substances present in the urine and the conditions prevailing during their formation. Kidney stones, are a common result of this process, with types including CaOx, calcium phosphate, and uric acid stones, which are caused by high concentrations of these substances in the urine [27].

The process of crystal formation is influenced by a multitude of factors, including the pH level of urine, the concentration of minerals that encourage stone formation, and the presence of inhibitors that hinder crystal growth. As crystals accumulate and grow, they can lead to the formation of urinary casts, which obstruct urine flow and promote further stone formation [28].

The development of effective strategies for the prevention and treatment of kidney stone disease depends on our understanding of the mechanisms that influence crystal formation and growth [29].

4.3 Crystal nucleation

The phenomenon of nucleation is a crucial aspect of crystal formation from a supersaturated solution. It involves the aggregation of solute molecules or ions to form a stable nucleus, which then serves as a basis for subsequent crystal growth. As a result, a crystal structure with a distinct lattice pattern is produced. Crystallization can occur in confined spaces within a solution, such as those present in certain regions of the nephron [30], and on surfaces such as cells and the extracellular matrix. Nucleation can occur through two main mechanisms: homogeneous nucleation, which arises spontaneously within the solution, and heterogeneous nucleation, which occurs on the surface of a foreign particle or solid surface [31].

4.4 Crystal growth

After nuclei formation, crystals grow by adding new molecules to the crystal lattice. The rate of growth depends on various factors, such as the concentration of salts that form stones, urine pH, and the presence of inhibitors or promoters of crystal growth [32]. Inhibitors of crystal growth, such as citrate and magnesium, help prevent crystal aggregation and growth by binding to crystal surfaces and inhibiting their further growth [33]. Promoters of crystal growth, such as calcium and oxalate, can facilitate the aggregation and growth of crystals by increasing their surface charge and promoting attachment to other crystals or surfaces [32].

4.5 Crystal aggregation

Over time, crystals can aggregate to form larger particles, which may lead to the formation of stones. The aggregation of crystals can be influenced by several factors, including the concentration and composition of the stone-forming salts, the pH of the urine, and the presence of organic and inorganic molecules that can act as bridging agents or inhibitors of crystal aggregation [32, 34]. The formation of stones can also be influenced by urine flow rates; slower flow rates allow for increased crystal aggregation and growth, whereas faster flow rates promote the flushing out of crystals, thereby preventing their aggregation [35].

4.6 Crystal-cell interaction

The interaction between crystals and renal epithelial cells is a critical factor in the pathogenesis of kidney stones. When crystals adhere to the cell surface, they can cause injury and inflammation. This process can further promote crystal growth and aggregation, as well as the recruitment of immune cells and the release of inflammatory mediators. The attachment of crystals to renal cells occurs through various mechanisms, including electrostatic interactions, surface receptors, and extracellular matrix proteins. Once attached, crystals can cause cellular injury through multiple pathways, such as membrane disruption, oxidative stress, and mitochondrial dysfunction. These changes lead to the release of danger signals and the activation of inflammatory pathways, further exacerbating crystal-induced injury and inflammation. The interaction between crystals, renal cells, and immune cells can also lead to the formation of urinary casts, which may obstruct urine flow and promote stone formation. In addition to renal epithelial cells, immune cells such as macrophages and T cells can contribute to the progression of kidney stone disease by releasing inflammatory cytokines and chemokines. This cycle of injury and inflammation can promote the growth and aggregation of stones, contributing to the development and progression of kidney stone disease [27].

5 Types of urolithiasis

Urinary stones are categorized into five major types.

5.1 Calcium oxalate stones

Calcium oxalate urolithiasis is the most prevalent form of urinary stone, accounting for roughly 50% of all cases [36]. Hypercalciuria, a condition often associated with calcium kidney stones, has an etiology that is still not fully understood. In order to impede the formation of CaOx stones, it is advisable to regulate urine chemistry through controlled modification of sodium, citrate, oxalate, uric acid, calcium, and specific gravity levels [37]. By adhering to a straightforward dietary plan that targets five urinary parameters, patients with idiopathic CaOx stone formation may reduce their urinary supersaturation. This plan places emphasis primarily on dilute urine concentration, diminishing crystallization promoters (via lowering oxalate), and elevating crystallization inhibitors (through increased citrate). Absorption of intestinal oxalate can be reduced through higher fluid intake and calcium consumption during meals [38].

There is evidence that high dietary calcium intake can expedite kidney stone development, while consuming low-calcium foods alongside oxalate-rich ones may decrease this risk [39]. Additionally, the development of uric acid and CaOx stones is substantially correlated with obesity, unlike stones comprising calcium phosphate or cystine [40]. The development of renal papillary calcifications shows relevance in prognostic ability in CaOx urolithiasis cases. Further research into these facets is merited to inform effective preventative strategies against stone formation [41].

5.2 Calcium phosphate stones

Calcium phosphate stones, a type of urolithiasis stone, constitute approximately 10–20% of all urinary stones [36], representing a significant global urological concern. Recent research has demonstrated that calcium urolithiasis often arises due to renal phosphate leakage and concomitant phosphaturia. Individuals with abnormally elevated levels of phosphate in their urine (known as hyperphosphaturia) are at a heightened risk for the recurrence of these stones [42].

5.3 Uric acid stones

Uric acid stones, a specific type of urolithiasis, comprise approximately 10% of all instances of urinary calculi. These radiolucent stones can be efficiently treated using endoscopic and chemotherapeutic techniques, as well as surgical interventions such as percutaneous nephrolithotomy and extracorporeal shock wave lithotripsy [43]. The etiology of uric acid urolithiasis is still not fully understood despite intensive investigation. Hyperuricosuria, consistently low urine pH, and low urinary volume are risk factors for the development of these stones. Diseases such as uncontrolled diabetes mellitus, gout, and leukemia, which cause hyperuricosuria are known to predispose individuals to uric acid urolithiasis [44]. Additionally, dietary modifications, including reduced salt intake and limited consumption of animal protein, have been demonstrated to be effective in preventing uric acid stones [45].

5.4 Struvite (magnesium ammonium phosphate) stones

Urinary tract stones known as struvite or magnesium ammonium phosphate stones can develop in the urinary tract. These stones often occur in individuals with urinary tract infections caused by bacteria that produce urease, such as Klebsiella or Proteus [46]. Although not as common as CaOx stones, this type of urinary stones constitutes approximately 10–15% of all cases. They are more prevalent in females and individuals with a history of recurrent urinary tract infections [47, 48]. Struvite stones, composed of ammonium, magnesium, and phosphate can form when urease produced by bacteria breaks down urea in the urine, resulting in a rise in pH and the formation of struvite crystals that can aggregate and form stones [49]. The prevention of struvite stones involves treating and preventing Urinary tract infections (UTIs) caused by bacteria that produce urease through antibiotic treatment and good hygiene practices [50]. Additionally, maintaining urinary tract health and adequate fluid intake can also help prevent the formation of struvite stones [51, 52]. Depending on their size and location, struvite stones require different treatments: small stones may pass spontaneously, whereas larger stones might necessitate medical intervention [53].

5.5 Cystine stones

Cystine stones, an uncommon form of kidney stone, form due to an inherited metabolic disorder called cystinuria. This disorder leads to an elevated concentration of cystine in the urine, which can crystallize and form stones in the kidneys, ureters, or bladder [54, 55]. Characterized by their yellowish-brown color and hexagonal shape, they are typically larger and harder than other types of kidney stones. The prevalence of cystinuria, the underlying cause of cystine stones, is estimated to be around 1 in 7,000 to 1 in 20,000 individuals worldwide. However, it varies among different ethnic groups, with higher rates reported in certain populations such as Ashkenazi Jews, Libyans, and Cypriots [56, 57]. Cystine stones consist of cystine, an amino acid that contains sulfur. Due to its low solubility, cystine tends to precipitate and form crystals in urine, resulting in the formation of cystine stones [58, 59]. The primary prevention of cystine stones involves managing cystinuria through dietary modifications and medical interventions, including maintaining a high fluid intake, adhering to a low-sodium diet, and avoiding excessive intake of animal protein [60, 61]. Medical therapy for cystinuria involves the use of medications such as alpha-mercaptopropionylglycine (tiopronin) or D-penicillamine, which help to reduce cystine concentration in the urine by forming soluble complexes with cystine [62]. Conservative management, pain management, and surgical intervention may also be necessary for the treatment of cystine stones [63, 64].

6 Kidney stone formation inhibitors

Significant progress has been made recently in the creation of inhibitors that target the formation of CaOx crystals, such as small molecules, peptides, and proteins [65, 66]. These inhibitors play a crucial part in preventing the pathological crystallization of CaOx crystals (Table 1). Notably, growth-inhibiting compounds with acidic moieties, including carboxylates, phosphates, and sulfates, have demonstrated remarkable suppression of calcium oxalate monohydrate (COM) crystal expansion, attributed to their specific association with Ca²⁺ ions on crystalline interfaces [65, 67, 68]. Moreover, synthetic peptides, polymers, and proteins have also exhibited significant COM crystal formation inhibition [67, 69]. However, it is noteworthy that the synthesis of these potent inhibitors primarily relies on synthetic methods, leading to substantial expenses and potential regulatory approval challenges [70, 71].

Table 1 Represents kidney stone inhibitors and their mechanisms

7 Promoters of increasing urolithiasis

Urolithiasis can emerge due to a diverse range of factors, involving genetic, environmental, and lifestyle influences. Some examples of these factors, along with their respective mechanisms of promoting urolithiasis, are provided in Table 2.

Table 2 Represents kidney stone promoters and their mechanisms

8 Conclusion

Urolithiasis presents a significant public health challenge, necessitating continued research to enhance our understanding and treatment of this condition. The pathophysiology of urolithiasis is a dynamic process involving a series of events, from supersaturation and nucleation to crystal aggregation and ultimately stone production. Numerous variables, such as the pH of the urine, crystal promoters and inhibitors, and anatomical variations, impact this condition. The exploration of potential inhibitors of calcium oxalate crystal formation shows promise in revolutionizing urolithiasis prevention strategies. Through a systematic approach that combines various modalities, we can effectively manage urolithiasis, thereby mitigating its impact on global health. The landscape of research is evolving, emphasizing the importance of genetics and molecular pathways, and opening exciting opportunities for future therapeutic approaches.