Role of atherosclerosis in pathogenesis of renal stone disease: Do all roads lead to Rome?

Yogendra Singh Gaharwar; Swapnil S Topale; Umar Farouqi; Bhattaram Surya Prakash

doi:10.4103/0971-9903.202014

REVIEW ARTICLE

Year : 2017 | Volume : 22 | Issue : 1 | Page : 4-7

Role of atherosclerosis in pathogenesis of renal stone disease: Do all roads lead to Rome?

Yogendra Singh Gaharwar¹, Swapnil S Topale¹, Umar Farouqi², Bhattaram Surya Prakash¹
¹ Department of Urology, Yashoda Hospitals, Hyderabad, Telangana, India
² Department of Urology, Max Hospital Patparganj, New Delhi, India

Date of Web Publication

14-Mar-2017

Correspondence Address:
Yogendra Singh Gaharwar
Department of Urology, Yashoda Hospital, Malakpet, Hyderabad - 500 036, Telangana
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/0971-9903.202014

Abstract

Urolithiasis is as old as human civilization. Ancient Egyptian mummies and Indian Ayurvedic descriptions are testimony to this fact. Despite such an old association with humanity pathogenesis of renal stone disease remains far from fully understood. Randall's plaques were believed to be as initiating lesions for calcium oxalate stone since Randall's original description in 1937. However, the origin of Randall's plaque is not fully understood. Till recently, it was thought that excursion of calcium oxalate crystals into basolateral membrane of tubular cells initiates inflammation and leads to calcification. Many exciting new papers though not denying this hypothesis point toward a role of vascular injury-atherosclerosis – calcifying nanoparticles in pathogenesis of Randall's plaque. Hence, renal stone disease may be a harbinger of cardiovascular pathology and vice versa.

Keywords: Atherosclerosis, calcifying nanoparticles, Randall's plaque, urolithiasis

How to cite this article:
Gaharwar YS, Topale SS, Farouqi U, Prakash BS. Role of atherosclerosis in pathogenesis of renal stone disease: Do all roads lead to Rome?. J Mahatma Gandhi Inst Med Sci 2017;22:4-7

How to cite this URL:
Gaharwar YS, Topale SS, Farouqi U, Prakash BS. Role of atherosclerosis in pathogenesis of renal stone disease: Do all roads lead to Rome?. J Mahatma Gandhi Inst Med Sci [serial online] 2017 [cited 2023 Mar 30];22:4-7. Available from: https://www.jmgims.co.in/text.asp?2017/22/1/4/202014

Introduction

Urinary stone disease is almost as old as human civilization. Stone disease inflicted ancient Egyptian civilization inhabitants. Egyptian mummies had revealed kidney and bladder stone disease.^[1] In India, Sushruta in 6^th Century, B.C. reported urolithiasis and its complications, such as infection, anuria, and uremia.^[2] Charaka in his Charak-Samhita mentions about instrumental removal of stone from urethra.^[2]

Despite such an old history pathogenesis and exact reasons for renal stone formation remain unclear. Great advances have been made in extraction/letting out the stone from urinary tract, but an exact understanding of pathogenesis of stone disease remains a far cry. In this article, we will review the literature and try to find out the recent understanding of the pathogenesis of renal stone disease.

Pathogenesis of Renal Stones

For formation of renal stone, two things are required one is supersaturated or metastable state in which crystals can precipitate and second is usually but not always the availability of an anchoring site for crystals to aggregate and become stone.^[3],[4],[5]

Physiochemical Theory

Stoller et al.^[3] pointed out that as the glomerular filtrate passes through the nephron, the urine becomes concentrated with stone-forming salts which, when supersaturated, can precipitate out of solution into crystals that can either be expulsed with voided urine or grow and aggregate under the relative influences of various stone-promoting or stone-inhibiting agents, resulting in stone formation.

Finlayson and Reid ^[5] pointed out the fallacies of Physicochemical theory. They argued that Physiochemical theory postulates that crystals formed can grow and obliterate tubular lumen and can become nidus for stone formation. The problem with above theory is that most researchers believe that a transit time of 5–7 min through nephron does not provide enough window of opportunity for crystals to grow into a size that is large enough to obliterate tubular lumen.

Fixed particle growth theory presupposes an anchoring site to which crystals bind, thereby prolonging the time the crystals are exposed to supersaturated urine and facilitating crystal growth and aggregation.^[6] Fixity of these crystals to epithelium is required for crystals to grow and aggregate. This is called as fixed particle theory.^[5]

There are some studies to support that even free floating crystals can grow to a large size to obliterate the tubular lumen and the size of tubular lumen is not as large as previously thought.^[7] Within the time frame of transit of urine through the nephron, estimated at 5–7 min, crystals cannot grow to reach a size sufficient to occlude the tubular lumen. However, if enough nuclei form and grow aggregation of the crystals will form larger particles within minutes that can occlude the tubular lumen,^[6] however, most research favors fixed particle theory.^[4]

When we search for an initiating lesion for renal stones, answer seems to lie in Randall's plaque hypothesis.

Randall ^[8] conducted autopsy in 429 pairs of kidney and found papillary lesions in 17%. On microscopic examination, this lesion was found to be a plaque of calcium deposited in interstitial tissue of renal papilla. By microscopic examination and special stains, Randall laid that “Here is microscopic evidence of a calculus of one chemical composition growing from the surface of an intra-papillary plaque of a different chemical composition.” Randall hypothesized that exposed plaque material served as a nidus for stone formation.

Miller et al.^[9] provided evidence for Randall's plaque theory. They did an endoscopy and analyzed 115 stones collected from 9 patients, and found only 25 stones not attached to renal papillae. Of these 25 stones, 4 were lost, and 12 showed definite morphological evidence of having been attached to tissue, probably having been knocked off of papillae during access of endoscope. For the remaining nine stones, which did not show morphological evidence of attachment they did micro-computed tomography analysis and found at least one internal region of calcium phosphate within each of these unattached calcium oxalate stones. They found that chemical structure of unattached stones is suggestive of their origin from renal papillae, and then having become detached but retained in the kidney, with new layers of calcium oxalate eventually covering the original attachment site. Based on these observations, Miller et al.^[9] concluded that “the plaque hypothesis is supported by this work, and has not as yet been contradicted by studies designed to falsify it; therefore, it can be accepted as a useful contemporary paradigm for planning future stone research.”

However, how these Randall plaques are formed remains an issue of debate.^[4] Evan et al.^[10] localized the origin of the plaque to the basement membrane of the thin limbs of the loops of Henle and demonstrated that the plaque subsequently extends through the medullary interstitium to a subepithelial location. Once the plaque erodes through the urothelium, it is thought to constitute a stable, anchored surface on which calcium oxalate crystals can nucleate and grow as attached stones.

Knoll et al.^[11] by their cell culture experiment demonstrated that sodium oxalate has a negative effect on the growth and survival of renal epithelial cells fibroblasts and endothelial cells. They also found that renal epithelial cells are more vulnerable to oxalate on their basolateral side. Based on these observations, they implicated interstitium as the primary site of plaque formation.

Stoller et al.^[12] however, lay that Randall's plaques are not merely subepithelial deposits. Rather, they appear to extend deep within the papilla and are intimately associated with collecting tubules and vasa recta.

These observations lead to vascular theory of plaque formation. The vascular theory of plaque formation is supported by three properties of renal physiology.

Turbulent blood flow at tip of Papilla due to 180° transition of vessels at papillary tip, predisposing area to vascular injury and atherosclerosis like reactions and subsequent plaque formation ^[4]
10-fold or higher increase in osmolality occurs between the renal cortex and the tip of the papilla which imposes deleterious effects on surrounding cells ^[13]
A decreasing gradient of oxygen-carrying capacity occurs from the renal cortex to the tip of the papilla.^[14]

These three factors can promote atherosclerosis like reaction.

Indirect evidence of the interaction between the vascular system and urinary stone formation has come from a study of Shekarriz et al.^[15] who reported an interesting finding that urinary stones tend to be largely unilateral and on the dependent sleeping side of patients. Shekarriz et al.^[15] while making these observations admitted that exact pathophysiology of the association between sleep posture and recurrent unilateral stone disease remains to be elucidated, and sleep posture may alter renal hemodynamics during sleep and promote stone formation Rubenstein et al.^[16] studied renal perfusion by scintigraphy in ten healthy volunteers and found that renal perfusion in the dependent kidney was increased when compared with the same kidney in the supine position in both the left and right kidneys.

Other evidence for vascular theory comes from various other studies.

Rule et al.^[17] in a study of more than 4500 stone formers compared with nearly 11,000 control patients with 9 years of follow-up found that nephrolithiasis is associated with a 31% increased risk of myocardial infarction.

Similarly Reiner et al.^[18] in their study of Coronary Adult Risk Development in Young Adult Cohorts reported a significant association between a history of kidney stones and subclinical carotid atherosclerosis in young adults. They held that this finding adds further support to the notion that nephrolithiasis and atherosclerosis share common systemic risk factors and/or pathophysiology.

Cappuccio et al.^[19] and Borghi et al.^[20] have found links between hypertension and risk of renal stone disease. The link between hypertension and urinary stone disease seems to be potentially bidirectional, as supported by studies that have demonstrated stone formation to predate the onset of hypertension. In their prospective study of a cohort of more than 50,000 men, Madore et al.^[21] noted an association between nephrolithiasis and risk of hypertension (odds ratio, 1.31), and reported that in men who had both disorders, 79.5% experienced the occurrence of nephrolithiasis before or concomitant to their diagnosis of hypertension.

A similar association was seen in women, with a relative risk of 1.36 for developing a new diagnosis of hypertension in those with a history of nephrolithiasis, as demonstrated from data secured from the Nurses' Health Study, a cohort with nearly 90,000 women. Madore et al.^[22] after examining data concluded that dietary factors, such as the intake of calcium, sodium, and potassium, do not explain this association. Unidentified pathogenic mechanisms common to nephrolithiasis and hypertension may be responsible for the development of both disorders.

Vascular theory of stone development is one hypothesis which attempts to link stone formation with obesity, diabetes, dyslipidemia, and metabolic syndrome.^[4] It considers a common pathway of systemic malfunction and inflammation and tissue damage as an underlying mechanism.^[4]

The Role of Calcifying Nanoparticles

Calcifying nanoparticles (CNPs), also known as nanobacteria, were discovered more than 25 years ago as cell culture contaminants. They were originally described as novel microorganisms and were isolated from human and bovine blood and blood products. They were characterized as fastidious and cytotoxic, and carbonate apatite–forming.^[23]

The nature of these particles has since been debated, with contrasting theories – some describing them as a self-replicating form of life, and others describing them as a nonliving physicochemical phenomenon in the form of mineral protein complexes.^[4]

Several investigators have isolated evidence of CNPs in 62%–100% of urinary stone samples in various studies.^{[23],[24],[25]} Similarly, serum studies of patients with nephrolithiasis have also noted evidence of CNPs, with Chen et al.^[26] evaluating a 27-patient cohort and showing CNPs in the serum of 92% of patients with nephrolithiasis, compared with 0% of controls.

The mechanism through which CNPs influence urinary stone disease has been suggested to be related to an etiologic role they may play in Randall plaques. This theory was supported by Ciftçioglu et al.^[23] who detected CNPs in more than 70% of kidney papillae samples with Randall plaques, while conversely noting that more than 80% of papillae samples without Randall plaques were free of CNPs.

Although the precise mechanisms through which CNPs may be related to urinary stone disease remain elusive, evaluation of their involvement with atherosclerotic disease and cardiovascular calcification may provide some clues. The links between CNPs and these forms of cardiovascular disease have been evaluated in multiple studies. Puskás et al.^[27] serologically identified CNPs in most atherosclerotic plaques they examined, whereas their presence was lacking in control areas of the same vessels. Furthermore, CNPs were extracted and cultivated from most calcified sclerotic aortic and carotid samples, suggesting their involvement in atherosclerotic pathogenesis and subsequent blood vessel calcification.

In an effort to investigate the nature of CNP arterial toxicity, Schwartz et al.^[28] exposed a rabbit model with unilaterally damaged carotid arteries to mineralized CNPs from kidney stones. Damaged arteries exposed to the CNPs became occluded and calcified, whereas the arteries with a healthy endothelium were resistant to exposure to the CNPs in this respect. These interesting findings note a connection between endothelial damage of blood vessels and calcification, with CNPs as a pathogenic factor. Although further studies are required to definitively establish association and theories of pathogenesis, this is one potential mechanism through which CNPs could be involved in the formation of urinary stones.

Conclusion

Recent research seemingly leads us to a common pathway of atherosclerosis manifesting as the initiator of stone disease in kidney and cardiovascular disease elsewhere. CNPs may be common agents for initiating calcification in Randall's plaque as well as atherosclerotic plaques.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Eknoyan G. History of urolithiasis. Clin Rev Bone Miner Metab 2004;2:177-85.
2.	López M, Hoppe B. History, epidemiology and regional diversities of urolithiasis. Pediatr Nephrol 2010;25:49-59.
3.	Stoller ML, Meng MV. Urinary stone disease. Totowa (NJ): Humana Press; 2007.
4.	Bagga HS, Chi T, Miller J, Stoller ML. New insights into the pathogenesis of renal calculi. Urol Clin North Am 2013;40:1-12.
5.	Finlayson B, Reid F. The expectation of free and fixed particles in urinary stone disease. Invest Urol 1978;15:442-8.
6.	Pearle MS, Lotan Y. Urinary lithiasis: Etiology, epidemiology & pathogenesis. In: Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA, editors. Campbell-Walsh: Urology. 10^th ed. Philadelphia: Saunders, an Imprint of Elsevier Inc.; 2012. p. 1262.
7.	Kok DJ, Khan SR. Calcium oxalate nephrolithiasis, a free or fixed particle disease. Kidney Int 1994;46:847-54.
8.	Randall A. The origin and growth of renal calculi. Ann Surg 1937;105:1009-27.
9.	Miller NL, Williams JC Jr., Evan AP, Bledsoe SB, Coe FL, Worcester EM, et al. In idiopathic calcium oxalate stone-formers, unattached stones show evidence of having originated as attached stones on Randall's plaque. BJU Int 2010;105:242-5.
10.	Evan AP, Lingeman JE, Coe FL, Parks JH, Bledsoe SB, Shao Y, et al. Randall's plaque of patients with nephrolithiasis begins in basement membranes of thin loops of Henle. J Clin Invest 2003;111:607-16.
11.	Knoll T, Steidler A, Trojan L, Sagi S, Schaaf A, Yard B, et al. The influence of oxalate on renal epithelial and interstitial cells. Urol Res 2004;32:304-9.
12.	Stoller ML, Low RK, Shami GS, McCormick VD, Kerschmann RL. High resolution radiography of cadaveric kidneys: Unraveling the mystery of Randall's plaque formation. J Urol 1996;156:1263-6.
13.	Kwon MS, Lim SW, Kwon HM. Hypertonic stress in the kidney: A necessary evil. Physiology (Bethesda) 2009;24:186-91.
14.	O'Connor PM. Renal oxygen delivery: Matching delivery to metabolic demand. Clin Exp Pharmacol Physiol 2006;33:961-7.
15.	Shekarriz B, Lu HF, Stoller ML. Correlation of unilateral urolithiasis with sleep posture. J Urol 2001;165:1085-7.
16.	Rubenstein JN, Stackhouse GB, Stoller ML. Effect of body position on renal parenchyma perfusion as measured by nuclear scintigraphy. Urology 2007;70:227-9.
17.	Rule AD, Roger VL, Melton LJ 3^rd, Bergstralh EJ, Li X, Peyser PA, et al. Kidney stones associate with increased risk for myocardial infarction. J Am Soc Nephrol 2010;21:1641-4.
18.	Reiner AP, Kahn A, Eisner BH, Pletcher MJ, Sadetsky N, Williams OD, et al. Kidney stones and subclinical atherosclerosis in young adults: The CARDIA study. J Urol 2011;185:920-5.
19.	Cappuccio FP, Siani A, Barba G, Mellone MC, Russo L, Farinaro E, et al. A prospective study of hypertension and the incidence of kidney stones in men. J Hypertens 1999;17:1017-22.
20.	Borghi L, Meschi T, Guerra A, Briganti A, Schianchi T, Allegri F, et al. Essential arterial hypertension and stone disease. Kidney Int 1999;55:2397-406.
21.	Madore F, Stampfer MJ, Rimm EB, Curhan GC. Nephrolithiasis and risk of hypertension. Am J Hypertens 1998;11 (1 Pt 1):46-53.
22.	Madore F, Stampfer MJ, Willett WC, Speizer FE, Curhan GC. Nephrolithiasis and risk of hypertension in women. Am J Kidney Dis 1998;32:802-7.
23.	Ciftçioglu N, Björklund M, Kuorikoski K, Bergström K, Kajander EO. Nanobacteria: An infectious cause for kidney stone formation. Kidney Int 1999;56:1893-8.
24.	Kutikhin AG, Brusina EB, Yuzhalin AE. The role of calcifying nanoparticles in biology and medicine. Int J Nanomedicine 2012;7:339-50.
25.	Kajander EO, Ciftçioglu N. Nanobacteria: An alternative mechanism for pathogenic intra- and extracellular calcification and stone formation. Proc Natl Acad Sci U S A 1998;95:8274-9.
26.	Chen L, Huang XB, Xu QQ, Li JX, Jia XJ, Wang XF. Cultivation and morphology of nanobacteria in sera of patients with kidney calculi. Beijing Da Xue Xue Bao 2010;42:443-6.
27.	Puskás LG, Tiszlavicz L, Rázga Z, Torday LL, Krenács T, Papp JG. Detection of nanobacteria-like particles in human atherosclerotic plaques. Acta Biol Hung 2005;56:233-45.
28.	Schwartz MA, Lieske JC, Kumar V, Farell-Baril G, Miller VM. Human-derived nanoparticles and vascular response to injury in rabbit carotid arteries: Proof of principle. Int J Nanomedicine 2008;3:243-8.