Background and Purpose: Percutaneous nephrolithotomy (PCNL) is considered the standard procedure for the removal of large renal calculi. The development of the “minimally invasive PCNL” (mini-PCNL) has reduced the complications of the surgery; it also appears to be associated with less morbidity than the conventional PCNL (con-PCNL). This study aimed at evaluating the efficacy of endoscopic intrarenal surgery, using the prone-split leg position, using flexible ureteroscopy and mini-PCNL (mini- endoscopic combined intrarenal surgery [ECIRS]) by retrospectively comparing this technique with mini-PCNL and con-PCNL. Patients and Methods: In total, 161 consecutive patients who were observed for the follow-up of large renal calculi between February 2004 and January 2013 were selected for mini-ECIRS (60), mini-PCNL (19), or con-PCNL (82). Mini-ECIRS was performed with patients in the prone split-leg position via 18F minipercutaneous tract and 14F ureteral access sheath. The mini-PCNL was performed via 18F percutaneous tract and con-PCNL performed via the 30F tract. Mean size of the renal calculi removed via mini-ECIRS, mini-PCNL, and con-PCNL were 39.2, 38.4, and 34.6 mm, respectively. Results: Average surgical time for mini-ECIRS was shorter than that for mini-PCNL and con-PCNL (120.5 vs 181.9 vs 134.1 min, respectively; P <0.001). The stone-free rate for mini-ECIRS was significantly higher than that of the other procedures (initial rates 81.7% vs 38.9% vs 45.1%, respectively; P <0.001; rates after further treatment 86.7% vs 61.1% vs 61.0%, respectively; P =0.002). Only one patient in the mini-ECIRS group needed blood transfusions. The decrease in hemoglobin during mini-ECIRS and mini-PCNL was significantly lower than that during con-PCNL ( P =0.011). Conclusion: Mini-ECIRS is better than monotherapy with mini-PCNL or con-PCNL. The study results show that mini-ECIRS is a safe, efficient, and versatile procedure that can be effective for the management of renal calculi.

In our previous report, M2-macrophage (Mφs) deficient mice showed increased renal calcium oxalate (CaOx) crystal formation; however, the role of Mφs-related-cytokines and chemokines that affect kidney stone formation remains unknown. Here, we investigated the role of M1/M2s in crystal development by using in vitro and in vivo approaches. The crystal phagocytic rate of bone marrow-derived M2Mφs was higher than that of bone marrow-derived Mφs and M1Mφs and increased on co-culture with renal tubular cells (RTCs). However, the amount of crystal attachment on RTCs reduced on co-culture with M2Mφs. In six hyperoxaluric C57BL/6J mice, M1Mφ transfusion and induction by LPS and IFN-γ facilitated renal crystal formation, whereas M2Mφ transfusion and induction by IL-4 and IL-13 suppressed renal crystal formation compared with the control. These M2Mφ treatments reduced the expression of crystal-related genes, such as osteopontin and CD44, whereas M1Mφ treatment increased the expression of pro-inflammatory and adhesion-related genes such as IL-6, inducible NOS, TNF-α, C3, and VCAM-1. The expression of M2Mφ-related genes was lower whereas that of M1Mφ-related genes was higher in papillary tissue of CaOx stone formers. Overall, our results suggest that renal crystal development is facilitated by M1Mφs, but suppressed by M2Mφs.

Background: The global prevalence and recurrence rate of kidney stones is very high. Recent studies of Randall plaques and urinary components in vivo, and in vitro including gene manipulation, have attempted to reveal the pathogenesis of kidney stones. However, the evidence remains insufficient to facilitate the development of novel curative therapies. The involvement of renal and peripheral macrophages in inflammatory processes offers promise that might lead to the development of therapeutic targets. The present systematic literature review aimed to determine current consensus about the functions of macrophages in renal crystal development and suppression, and to synthesize evidence to provide a basis for future immunotherapy.Methods: We systematically reviewed the literature during February 2021 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles investigating the relationship between macrophages and urolithiasis, particularly calcium oxalate (CaOx) stones, were extracted from PubMed, MEDLINE, Embase, and Scopus. Study subjects, languages, and publication dates were unrestricted. Two authors searched and screened the publications.Results: Although several studies have applied mixed modalities, we selected 10, 12, and seven (total, n = 29) of 380 articles that respectively described cultured cells, animal models, and human samples.The investigative trend has shifted to macrophage phenotypes and signaling pathways, including micro (m)-RNAs since the discovery of macrophage involvement in kidney stones in 1999. Earlier studies of mice-associated macrophages with the acceleration and suppression of renal crystal formation. Later studies found that pro-inflammatory M1- and anti-inflammatory M2-macrophages are involved. Studies of human-derived and other macrophages in vitro and ex vivo showed that M2-macrophages (stimulated by CSF-1, IL-4, and IL-13) can phagocytose CaOx crystals, which suppresses stone development. The signaling mechanisms that promote M2-like macrophage polarization toward CaOx nephrocalcinosis, include the NLRP3, PPARγ-miR-23-Irf1/Pknox1, miR-93-TLR4/IRF1, and miR-185-5p/CSF1 pathways.Proteomic findings have indicated that patients who form kidney stones mainly express M1-like macrophage-related proteins, which might be due to CaOx stimulation of the macrophage exosomal pathway.Conclusions: This systematic review provides an update regarding the current status of macrophage involvement in CaOx nephrolithiasis. Targeting M2-like macrophage function might offer a therapeutic strategy with which to prevent stones via crystal phagocytosis.

We recently reported evidence suggesting that migrating macrophages (Mϕs) eliminate renal crystals in hyperoxaluric mice. Mϕs can be inflammatory (M1) or anti-inflammatory (M2), and colony-stimulating factor-1 (CSF-1) mediates polarization to the M2Mϕ phenotype. M2Mϕs promote renal tissue repair and regeneration, but it is not clear whether these cells are involved in suppressing renal crystal formation. We investigated the role of M2Mϕs in renal crystal formation during hyperoxaluria using CSF-1–deficient mice, which lack M2Mϕs. Compared with wild-type mice, CSF-1–deficient mice had significantly higher amounts of renal calcium oxalate crystal deposition. Treatment with recombinant human CSF-1 increased the expression of M2-related genes and markedly decreased the number of renal crystals in both CSF-1–deficient and wild-type mice. Flow cytometry of sorted renal Mϕs showed that CSF-1 deficiency resulted in a smaller population of CD11b⁺F4/80⁺CD163⁺CD206^hi cells, which represent M2-like Mϕs. Additionally, transfusion of M2Mϕs into CSF-1–deficient mice suppressed renal crystal deposition. In vitro phagocytosis assays with calcium oxalate monohydrate crystals showed a higher rate of crystal phagocytosis by M2-polarized Mϕs than M1-polarized Mϕs or renal tubular cells. Gene array profiling showed that CSF-1 deficiency resulted in disordered M2- and stone-related gene expressions. Collectively, our results provide compelling evidence for a suppressive role of CSF-1 signaling in renal crystal formation.

To clarify metabolic syndrome induced stone formation mechanisms we investigated the metabolic and immunohistochemical characteristics associated with renal crystal deposition using a model of mice with metabolic syndrome administered a high fat diet and ethylene glycol. Ob/Ob mice with Leptin gene deficiencies and metabolic syndrome related characteristics were compared with wild heterozygous lean mice. Four study groups were fed standard food and water (control group), a high fat diet and normal water (high fat diet group), 1% ethylene glycol and standard food (ethylene glycol group) or a high fat diet and 1% ethylene glycol (high fat diet plus ethylene glycol group). Blood, urine and kidney samples were taken after 14 days. Ob/Ob mice in the high fat diet plus ethylene glycol group showed diffuse renal crystal depositions. Lean and Ob/Ob mice in the high fat diet plus ethylene glycol group showed significant excretion of urinary calcium oxalate crystals. Ob/Ob mice had significant hypercalciuria, hyperphosphaturia and hyperlipidemia, massive lipid fragments in tubular lumina and fat droplets in renal tubular cells. Ob/Ob mice in the high fat diet plus ethylene glycol group had markedly increased expression of osteopontin, monocyte chemoattractant protein-1, interleukin-6 and tumor necrosis factor-α. In Ob/Ob mice the number of proinflammatory macrophages was considerably elevated. We induced renal crystal deposition in mice with metabolic syndrome using a high fat diet and ethylene glycol. Increases in luminal mineral and lipid density, and proinflammatory adipocytokines and macrophages facilitated renal crystal formation in mice with metabolic syndrome.