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Table of Contents
REVIEW ARTICLE
Year : 2019  |  Volume : 30  |  Issue : 5  |  Page : 200-205

Randall's plaque, the origin of nephrolithiasis: Where do we stand now?


Department of Urology, China Medical University Hospital, Taichung, Taiwan

Date of Submission15-Dec-2018
Date of Decision10-Feb-2019
Date of Acceptance11-Mar-2019
Date of Web Publication24-Oct-2019

Correspondence Address:
Wen-Chi Chen
Department of Urology, China Medical University Hospital, No. 2, Yuh-Der Road, North District, Taichung
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/UROS.UROS_144_18

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  Abstract 


The prevalence of renal stones, or nephrolithiasis, has been increasing consistently over the past few decades. Changes in lifestyles and dietary habits of the population may be responsible for the rise. Moreover, chronic diseases such as diabetes, hypertension, obesity, and metabolic syndrome are significant risk factors for renal stone formation. The 5-year recurrence rate of renal stones is around 50%. Those affected have a higher risk of comorbidities such as recurrent urinary tract infections, chronic kidney disease, and even end-stage renal disease. There is exciting ongoing research into newer treatments for renal stones. Currently, the prevailing hypothesis is that renal stones originate from Randall's plaques, which are patches of creamy-yellow calcium deposits found attached to the renal pelvis. However, the early steps involved in stone formation are still unclear. With the help of advanced technology and newer modalities, we can now observe the formative events upstream to actual stone formation. There are two recently updated theories that detail the biochemical events and structural changes that occur during this initial period. These well-designed works have expanded our awareness of Randall's plaques and provided direction for further research.

Keywords: Biomineralization, Randall's plaque, renal calculi, renal stone, stone formation


How to cite this article:
Tsai LH, Chang CH, Chen SJ, Chen WC. Randall's plaque, the origin of nephrolithiasis: Where do we stand now?. Urol Sci 2019;30:200-5

How to cite this URL:
Tsai LH, Chang CH, Chen SJ, Chen WC. Randall's plaque, the origin of nephrolithiasis: Where do we stand now?. Urol Sci [serial online] 2019 [cited 2019 Nov 22];30:200-5. Available from: http://www.e-urol-sci.com/text.asp?2019/30/5/200/268967




  Introduction Top


Urinary stone disease is considered one of the earliest recognized human disorders. Its origin can be traced back 7000 years, to ancient Egypt.[1] A calcium oxalate (CaOx) calculus is the major type of kidney stone occurring throughout the world. The rise in the prevalence of CaOx stones is evident, as they are now found in 70%–90% of all patients with kidney stones according to epidemiological data from Asia and Europe.[2],[3] While there has been considerable progress in treatments for kidney stones, the relatively uncomplicated procedure of lithotripsy is preferred by most urologists. As we have not yet deciphered the complete pathophysiology of renal stone formation, older knowledge of the process remains unchanged. Low fluid intake and an imbalanced diet are the two most recognized risk factors for stone formation.[4] Kidney stones that develop secondary to specific metabolic or genetic disorders or drugs represent only 10% of cases in the general population; most patients present with renal calculi that are idiopathic in origin. Stone formation is associated with disorders that cause hypercalciuria, hyperoxaluria, or hypocitraturia. It is postulated that the increased levels of poorly soluble salts in the circulation coupled with dehydration induce stone formation. Coe et al. proposed three principal mechanisms of stone formation.[5] First: free solution crystallization, in which homogeneous nucleation takes place in the urine instead of on the papillary surface (as occurs during cysteine stone formation). Second: formation of crystalline deposits in renal tubules and heterogeneous nucleated deposition of crystals in the ducts of Bellini and inner medullary collecting ducts of patients suffering from hyperoxaluria or renal tubular acidosis. Third: overgrowth of interstitial apatite plaques with nucleation on the renal papillary Randall's plaques. This final pathway is common in idiopathic CaOx stone formation. These kinds of stones usually have an inner layer containing calcium apatite and an outer layer containing CaOx.[6]


  Historical Description of Randall's Plaque and Plaque Progression to Stones Top


In 1937, Alexander Randall discovered previously unknown plaques within the intertubular spaces of renal papillae, following an examination of 1154 pairs of autopsied kidneys.[7],[8] He described the papillary lesions as “cream-colored” or “milk-patch” areas, composed of calcium phosphate (CaP) and calcium carbonate. The lesions often grew from the subepithelial layer, that is, from below the surface. He also found small CaOx calculi attached to the lesions after they had broken through the pelvic epithelium. These plaques served as nidi for renal stones and were termed Randall's plaques. Epidemiological reports have shown the presence of these plaques in 44%–57% of patients with renal calculi.[9],[10] A previous study using flexible ureteroscopy also found a higher prevalence rate of Randall's plaques in stone formers compared with nonstone formers (54% vs. 27%).[11] The actual prevalence might be higher, but because modern lithotripsy technique usually involves laser treatment and fragmentation, intact residual plaques are often not able to be identified in the collected remnants. After treatment, the fragmented stones often exhibit one smooth facet corresponding to the papillary surface, a phenomenon known as umbilication.[12] This natural concavity, which was first discovered by Cifuentes Delatte et al., provides strong evidence of the papillary origin of renal calculi.[13] Randall's plaques are primarily composed of CaP. The course from plaque to stone formation appears to be exceptionally complex, involving interactions of various anions that are driven by pH and concentration gradients. Multiple precursors of CaP exist, with carbonated apatite being the predominant example. This compound is the least soluble of all CaP precursors and tends to precipitate in alkaline environments. It can form spherical CaP structures which continue to aggregate into larger crystals in supersaturated urine. Once Randall's plaque erodes through the surface of the papilla, it acts as a nidus of crystallization for other particles. Other common precursors include hydroxyapatite, derived from brushite, and octacalcium phosphate. Gambaro et al. reported the finding of a “calcium stalk” or “stem” that had broken through the renal papilla and then attached to the stone.[14] Further analysis revealed that >90% of the stalks consisted of CaP, a similar composition to that of Randall's plaques.[15] Since Randall's extraordinary finding, scientists began to focus on research concerning the pathogenesis of the plaque. Although many theories have been postulated about the origin of Randall's plaques, we are still unsure whether they originate from the loop of Henle, vasa recta, or the collecting ducts.

Haggitt and Pitcock performed electron microscopy on randomly selected cadaver kidneys and found calcium-containing crystals in the renal interstitium adjacent to the basement membranes of the collecting ducts.[16] Cooke examined 62 normal kidneys and theorized that calcification could start in the loop of Henle, with involvement of the blood vessels.[17],[18] Evan et al. observed the renal papillae of stone formers and discovered that idiopathic stones grew and attached to Randall's plaques beyond the epithelium of the papillae.[19] The most comprehensive hypothesis of stone formation from plaques is the “Anderson–Carr–Randall progression” described by Bruwer.[20] This theory was derived from a combination of Anderson's and Carr's histology and microradiography findings[21],[22] and describes the initial formation of crystal “droplets” around the calcium-abundant renal tubules following phagocytosis and absorption of microcalculi by cells such as macrophages. The macrophages are passed down with lymph flow and aggregate in the distal renal papillae beneath the epithelium and later evolve into Randall's plaques. However, there is still no empirical evidence to support the existence of a pathway from proximal interstitial calcification to the formation of distal plaque deposits.


  The Medullo-Papillary Complex and the Mechanism of Biomineralization Top


There are many prevailing theories explaining the mechanism of biomineralization in the medullo-papillary complex. The two main theories are the pressure gradient and the vas washdown theories.

Pressure gradient theory

Each human kidney contains 8–12 parabolic structures that form the medullo-papillary complex. The complex consists of uriniferous and vascular tubules of varying lengths and diameters. It acts as a biofilter that exchanges ions, water, and metabolic deposits and facilitates urine formation.[23] The medullo-papillary complex can be separated into three zones, based on the position of the segments of the loop of Henle. Zones 1 and 2 are located at the outer medulla, along with the descending vasa recta. Within these zones, the vasa recta are surrounded by smooth muscle cells. Zone 3 is located at the inner medulla, where pericytes replace the muscle cells.[24] Previous studies have shown that the pericytes have mesenchymal stem cell-like characteristics, including osteogenic properties.[25] Within the complex, there are long- and short-loop nephrons, depending on the length of the loop of Henle. Long-loop nephrons are usually located in the central part of the complex, whereas the short-loop nephrons are located more peripherally due to their parabolic shape. Only the long-loop nephrons contain the thin ascending limbs that are able to reach the third zone. The relation of tubules and vessels, as well as their permeability to ions and water, varies considerably between the three zones. This unique tubulovesicular architecture leads to differing pressure and chemical gradients both longitudinally and transversely. The pressure in Zone 1 is higher than that in Zone 3, with the centrally located long-loop nephron presenting higher pressure gradients than the peripherally located short-loop nephron.[26] Conversely, the osmotic pressure increases inward from Zone 1 to Zone 3. The pressure changes are generated and maintained by the exchange of sodium, urea, and water.[27]

Coupled with the unique structure, a phenomenon described in physics may contribute to initial stone formation. Poiseuille's law describes the relationship between fluid flow rate, pressure, and radius of laminar flow, using Poiseuille's equation as follows:



Where Q = flow, P = pressure, r = radius of tubule, ŋ = fluid viscosity, and l = length of tubule.

According to this equation, flow rate through a tube is directly proportional to the pressure and fourth power of the radius but is inversely proportional to fluid viscosity and length of the tube. Poiseuille's law establishes that the flow rate of a saturated fluid in a tube is fastest in the center and slower when approaching the walls, which may explain why particles in a fluid tend to accumulate along the wall. Hsi et al. proposed the novel hypothesis of biomineralization upstream to nephrolithiasis.[28] This theory applies Poiseuille's law at two different levels: at the tubules and in the interstitial space. At the level of the tubules, pressure gradients in the short-loop nephrons located peripherally in Zones 1 and 2 are lower than those in the long-loop nephrons, which result in reduced flow velocity in the former. Therefore, when exposed to supersaturated urine, an increased number of particles accumulate along the walls of the tubule. As the solutes are continually deposited, the tubules of the peripheral loop nephrons become obstructed. Following this malfunction, the fluid volume is shunted to the central loop nephrons, where Poiseuille's law again comes into play. The intratubular pressure rises significantly as the total functional volume of the tubule decreases, and even, a small change in the radius of the tube can result in an enormous pressure differential due to the fourth-power relationship. This elevated pressure creates an interface between Zones 2 and 3, around the junction of the thin and thick loops of Henle. It is further postulated that differing tubular diameters lead to altered tubular pressure, known as the “Venturi effect.” The Venturi effect modifies steady urine flow to an active state. The urine flow velocity accelerates when the urine passes through narrower parts of the tubule (for example, the transition from large to small then back to large-diameter tubules, when fluid passes from the proximal straight tubule to the loop of Henle and onward through the thick ascending tubule.) The pressure effect can lead to circumferential strain. Continuous exposure to circumferential stress or hoop stress represents a force acting along the length of the cylinder and can cause the renal tubules and interstitium to become stiff. This induces the pericytes near the tip of the medullo-papillary complex to differentiate into an osteoblastic cell type. When this transformation occurs in the high chemical gradient of the medullary environment, it comprises the first step toward Randall's plaque formation.

Recent studies using micro X-ray computed tomography (microXCT) have provided evidence that support the biomineralization theory. The imaging technology of microXCT was first introduced in the 1980s but has only been used for the study of nephrolithiasis from 2000. It utilizes the difference in X-ray attenuation of each component to provide a thorough analysis of the stone structure [Figure 1]. Hsi et al. examined the medullo-papillary complexes of 12 patients following nephrectomy for a renal tumor. Their study utilized microXCT to analyze the density and structure of the mineral deposits, which revealed a sequential correlation between the proximal and distal mineralization. The interstitial deposits at the papillary tips were always associated with the presence of proximal, peripheral, and intratubular biominerals.[28] Chen et al. further examined the relationship between renal tubules and vasculature and studied the role of noncollagenous proteins (NCPs) in kidney mineralization using microXCT, electron microscopy, and immunolocalization techniques targeted toward specific proteins.[29] The authors reported NCPs to play an indispensable role in bone formation and published the first illustration of mineral deposits distal to the papillary tip in the medullo-papillary complex. These images provided fresh insights into the involvement of NCPs in biomineralization. Ho et al. completed three-dimensional landscapes of the kidney with the usage of microXCT.[26] Their proposed model explains the detailed structure of the medullo-papillary complex including the difference between the three zones and the fundamental architectural variations between intratubular and interstitial mineral deposits. The authors also identified a mineral-free transition area between the proximal and distal locations. Their study confirmed the theory of intratubular pressure differences causing circumferential strain, in turn leading to the formation of interstitial crystal deposits around the distal tubule – a cascade of events that occurs due to proximal tubular obstruction.
Figure 1: Microcomputed tomography images of the renal papilla from single patient nephroscopic biopsy. (a) Three-dimensional microcomputed tomography scan. (b) Three-dimensional microcomputed tomography scan with calcium oxalate crystals indicated by red dots. Some red spots are spread randomly in tissue, whereas some aggregated crystals form a tubular structure

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Vas washdown theory

Evan et al. recently published another novel hypothesis about the process of Randall's plaque formation.[30] They examined papillary biopsy specimens obtained from 15 hypercalciuric idiopathic stone formers during percutaneous nephrolithotomy. They suggested that Randall's plaques may originate from the thin ascending limb of the loop of Henle. The thick ascending limbs at the medulla normally only reabsorb calcium ions, which then enter the descending vasa recta. In hypercalciuric patients, an increased amount of calcium ions is reabsorbed and passed into the vasa recta. The vessels transport the extra calcium ions to the deep medulla, creating an environment of calcium supersaturation that, over time, fosters plaques. There are three types of tubules in the deep medulla: the collecting duct and the ascending and descending loops of Henle. The study of Evan et al. found that only the ascending loop of Henle is involved in Randall's plaque formation. The main difference between the ascending and descending loops is their permeability to water. The thin descending loops have good water permeability, enabling water to be extracted from the tubules when the interstitial osmotic pressure increases. Therefore, the interstitium around the descending loop of Henle does not reach supersaturation. Conversely, the ascending thin loops are impermeable to water. Therefore, when a high load of calcium ions washes down through the vasa recta, with no water to dilute its effect, the interstitium around the ascending loop reaches supersaturation easily, leading to the gradual emergence of plaques.

Evan et al. used immunolocalization to prove this hypothesis. They targeted two transport proteins: aquaporin-1 (AQP-1), found only in descending thin limb, and a chloride ion channel homolog (CLC-Ka), found only in ascending thin limb, and identified plaques using Yasue stain.[31] The results showed a strong correlation between sites that stained positively with Yasue and CLC-Ka stains. No plaque formation was detected on the tubules that tested positive for AQP-1. This finding implies that the plaques preferentially form in the ascending but not descending thin loops of Henle. They also determined that Randall's plaques originate from the basement membrane of the ascending tubules. This well-designed study was the first to pinpoint the exact location of origin of Randall's plaques and revealed potential pathways for further research into early treatment modalities for stone formers.

Other theories

One of the most controversial issues in previous assumptions relating to Randall's plaques is the location of initial plaque particulates. The first theory implicated that the contents of the thin loop of Henle are the cause of interstitial supersaturation. Evidence obtained from puncture biopsies in animal studies have shown CaP hypersaturation within the thin loop of Henle, thus supporting the theory.[32] However, further research revealed the thin loop of Henle to poor calcium permeability, so elevation of the calcium level inside the loop does not appear to be related to stone formation.[33] The animal study described possible calcium reabsorption at the collecting duct. However, no study to date has observed plaque formation in the collecting ducts.

Renal papillary vasculature also appears to play a critical role in renal stone formation. Taylor et al. proposed that plaques start as calcifications in the vasa recta.[30] Through CD31 staining, Chen et al. confirmed that the proximal intratubular mineralization resulted from the vasa recta.[29] NCPs are a group of unique organic tissue proteins including osteopontin (OPN), bone sialoprotein (BSP), and osteocalcin,[34],[35] which are present in the bone extracellular matrix and within renal calculi. Early reports found that NCPs accumulate in areas that demonstrate a high degree of mineralization.[29],[35] The distribution of NCPs is not anatomically specific, and the proteins may be delivered to various locations through the vasa recta. Anin vitro study has shown how the production and accumulation of BSP and OPN lead to tissue calcification.[36],[37],[38] While the localization of OPN in Randall's plaques and renal stones has been noted, unraveling the exact role and active isoforms assumed by the NCPs during stone formation remains a significant challenge.

The “free-particle mechanism” theory first proposed by Finlayson and Reid[39] describes how CaOx and CaP crystals nucleate and aggregate within the urine of renal tubules. Crystals may grow within continually hypersaturated urine and obstruct the renal tubules, forming occluding deposits termed Randall's plugs. The plugs may protrude out of the opening of the tubule or may be retained inside the kidney. When tubules are completely plugged, the urine within the tubules remains in stasis and the plugs serve as nidi of eventual stone formation.[40],[41] Evidence supporting this mechanism is derived from animal models andin vitro studies,[42],[43] which confirm that CaOx and CaP crystals could accumulate and grow in renal tubules, especially at points where urine flow is impeded during experimentally induced hypersaturation. The common sites involved include the junction between the proximal tubule and loop of Henle, the U-shaped bend of the loop, and the openings of the collecting tubules inside the renal pelvis (as the diameter is smaller than the lumen). Injury to the epithelium of the renal tubules and consequent sloughing are common during plug formation.[44] One significant difference between Randall's plugs and plaques is the position of the deposits; plugs are tubular deposits that are continuously exposed to urine, whereas plaques are interstitial deposits that form beyond the epithelium.


  Conclusion Top


The pathophysiology of nephrolithiasis is poorly understood, and different theories have been proposed regarding the origin of Randall's plaques, which are precursors to stone formation. Since Randall first discovered the plaques 80 years ago, research has failed to determine conclusively whether they originate from the basement membrane of the loop of Henle, the vasa recta, the collecting duct, or within the renal interstitium. With the help of advanced imaging techniques, such as microXCT and electron microscopy, we can now use histomorphometric approaches to study the details of uriniferous tubules and renal vasculature, with the aim of determining the exact process of plaque formation. We can also analyze the distribution and architecture of different ions and NCPs within the medullo-papillary complex. Two new and exciting studies by Evan and Stoller et al. have provided novel insight into the process of Randall's plaque formation while validating previous research in the area. It is through their outstanding results that we can begin to understand the biological cascade that results in the formation of renal stones. Once the calculus becomes visible in the renal pelvis, the process is irreversible. The pathological changes that occur upstream to the stone may be more critical to successful treatment of renal stones, and a therapeutic target may be hidden within the factors responsible for fostering these initial plaques.

Further studies are needed to answer a few major questions. First, why is there a difference in the chemical composition of renal stones between patients with Randall's plaques and those without? Second, what are the exact roles and the active isoforms of the NCPs involved in the mineralization process? Third, do Randall's plaques develop in other types of stones as well? Finally, can we utilize the decoded pathophysiology of the plaques to design newer, more effective, and early treatment modalities for patients presenting with stone formation? Solving the puzzle of the origin of Randall's plaques could completely revolutionize the future of nephrolithiasis treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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