Kidney stones are a major health burden and have high economic cost in the United States and abroad. Both are due to the treatment and constraint of work productivity (1). The underlying pathophysiologic mechanisms of “idiopathic calcium stone formation” are complex. Numerous mechanisms have been proposed for calcium stone formation. It has initially been suggested that the increased supersaturation of stone-forming salts is responsible for the homogenous nucleation in the lumen of the nephron, which is followed by crystal growth, culminating in an obstruction of the distal nephron. Second, it has been suggested that crystals that form in the renal tubular lumen adhere to luminal renal tubular cells, inducing renal tubular cell injury and resulting in the formation of fixed nuclei that interact with the supersaturated urinary environment, which results in crystal growth (2).
Alexander Randall (3) was the first to argue that intraluminal plugging is an infrequent occurrence in kidney stone formers. He suggested that interstitial calcium phosphate deposits are initial niduses that anchor urinary crystals under the normal uroepithial cells of the renal papilla. An earlier study by Khan and Kok (4) supported the association between inflammation and kidney stone disease. However, the proof of concept was not fully elucidated until recent studies utilizing kidney tissue from humans and animal models of calcium oxalate stones showed the abundance of expression of genes related to altered immune response in inflammation (5). These studies led to the suggestion that immune mechanisms via inflammatory cells and, principally, macrophages could be involved in the calcification process in response to urinary crystals presentation to monocytes, activating macrophages and contributing to crystals phagocytosis in patients with idiopathic nephrolithiasis (6). In a well-designed study published in this issue of CJASN by Dejban et al. (7), for the first time in a cross-sectional case-control study using nontumor nephrectomy tissue, samples levels of renal cortical and medullary calcium deposits were compared between various immune cell populations in both the kidney stone– and nonstone-forming populations. The results demonstrated that renal medullary calcification was higher in kidney stone formers than in nonstone formers. Furthermore, they demonstrated that the abundance of M1 macrophages (proinflammatory) was associated with renal medullary calcification in stone formers compared with nonstone formers and showed the association between M2 macrophages (anti-inflammatory) and renal cortical calcification in nonstone formers. However, there was no major contribution of other immune cell types, including T lymphocytes and mast cells, in the medullary and cortical renal calcification between these two populations.
In this model, the innate immune response is exerted via urinary crystals presentation to M2 macrophages; this process is similar to phagocytosis leading to crystals phagocytosis (8,9). However, the stimulation of adaptive immune mechanisms may lead to overzealous inflammatory responses by recruiting M1 macrophages (inflammatory), leading to renal medullary and cortical calcification in stone formers versus nonstone formers (Figure 1). The participation of innate and adaptive immunity was demonstrated in previous in vitro studies (10) showing activation of M2 macrophages (anti-inflammatory) with crystal phagocytosis and activation of monocyte differentiation to M1 macrophages (inflammatory) with short- and long-term calcium oxalate crystal exposure, respectively. The imbalances in adaptive immune responses will lead to increased production of proinflammatory cytokines, including TNFα, IL-1β, IL-8, and IL-10. This immune process will result in renal tubular epithelial cell injury, calcium oxalate crystal adhesion, and growth within the papillary and medullary regions of the kidney in the stone-forming population. Both clinical and in vitro studies have supported the implications of these pathways in the pathogenesis of kidney stone formation. In one study, the expression of M1 macrophages within the renal papillary tissue of a stone former was significantly higher than in an age- and sex-matched noncontrolled study (5). Moreover, the expression of M1-related genes was proven to be associated with stone formation, and in contrast, the expression of M2 macrophages was demonstrated to be associated with decreased stone formation (10). Whether the activation of macrophages and inflammatory response is associated with extrarenal production of calcitriol that affects intestinal calcium absorption and, at the same time, attenuates adaptive immunity, which then blunts inflammatory responses in the kidney stone population, should be further explored.
;)
Figure 1.: The imbalances between proinflammatory and anti-inflammatory cytokines in the pathogenesis of renal medullary calcification in patients with calcium nephrolithiasis.
The present study is an important initial step in the understanding of the possible role of both innate and adaptive immune responses and inflammation processes in the pathogenesis of kidney stone formation in the idiopathic calcium stone–forming population. One major limitation of the study is the lack of availability of longitudinal data vital in defining kidney stone characteristics, including kidney stone composition, severity of kidney stone recurrence, prior urologic procedures, and the use of antibiotics. Another limitation of the study was the lack of acquisition of longitudinal data describing in detail the characteristics of the population studied. The lack of knowledge of kidney stone composition and detailed information, including the severity of the illness and prior medical treatment, is a major shortcoming of this study. It is also difficult to understand why the macrophage population is different in response to crystal formation or if this difference reflects other potential physiologic response differences between the two populations preceding crystal formation. As it stands, both populations had the same level of calcification but different macrophage types. I believe that future detailed prospective mechanistic studies must be conducted to substantiate the causality of involvement of immune response and inflammation in the pathogenesis of calcium kidney stone formation. Future studies should not only be limited to the involvement of these novel pathways described by the investigators but also should include the elucidation of “downstream” mechanisms involved in crystal adhesions and growth.
Disclosures
The author has nothing to disclose.
Funding
None.
Acknowledgments
The content of this article reflects the personal experience and views of the author(s) and should not be considered medical advice or recommendation. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or CJASN. Responsibility for the information and views expressed herein lies entirely with the author(s).
The author would like to thank Rubyth Aguirre for her clerical assistance in the preparation of this manuscript.
Author Contributions
K. Sakhaee wrote the original draft and reviewed and edited the manuscript.
References
1. Romero V, Akpinar H, Assimos DG: Kidney stones: A global picture of prevalence, incidence, and associated risk factors. Rev Urol 12: e86–e96, 2010
2. Evan A: Histopathology predicts the mechanism of stone formation. In: Renal Stone Disease: 1st Annual International Urolithiasis Research Symposium (AIP Conference Proceedings), edited by Evan AP, Lingeman JE, Williams Jr. JC, New York, American Institute of Physics, 2007, pp 15–34
3. Randall A: Papillary pathology as a precursor of primary renal calculus. J Urol 44: 580–589, 1940
4. Khan SR, Kok DJ: Modulators of urinary stone formation. Front Biosci 9: 1450–1482, 2004
5. Taguchi K, Hamamoto S, Okada A, Unno R, Kamisawa H, Naiki T, Ando R, Mizuno K, Kawai N, Tozawa K, Kohri K, Yasui T: Genome-wide gene expression profiling of Randall’s plaques in calcium oxalate stone formers. J Am Soc Nephrol 28: 333–347, 2017
6. Kusmartsev S, Dominguez-Gutierrez PR, Canales BK, Bird VG, Vieweg J, Khan SR: Calcium oxalate stone fragment and crystal phagocytosis by human macrophages. J Urol 195: 1143–1151, 2016
7. Dejban P, Wilson EM, Jayachandran M, Herrera Hernandez LP, Haskic Z, Wellik LE, Sinha S, Rule AD, Denic A, Koo K, Potretzke AM, Lieske JC: Inflammatory cells in nephrectomy tissue from patients without and with a history of urinary stone disease. Clin J Am Soc Nephrol 17: 414–422, 2022
8. Hewison M: An update on vitamin D and human immunity. Clin Endocrinol (Oxf) 76: 315–325, 2012
9. Williams GR, Fierens K, Preston SG, Lunn D, Rysnik O, De Prijck S, Kool M, Buckley HC, Lambrecht BN, O’Hare D, Austyn JM: Immunity induced by a broad class of inorganic crystalline materials is directly controlled by their chemistry. J Exp Med 211: 1019–1025, 2014
10. Dominguez-Gutierrez PR, Kusmartsev S, Canales BK, Khan SR: Calcium oxalate differentiates human monocytes into inflammatory M1 macrophages. Front Immunol 9: 1863, 2018
