Explore the vast range of titles available.

Objectives To compare sodium ( 23 Na) characteristics between native and transplanted kidneys using dual-tuned proton ( 1 H)/sodium MRI. Methods Six healthy volunteers and six renal transplant patients (3 normal function, 3 acute allograft rejection) were included. Proton/sodium MRI was obtained at 3 T using a dual-tuned coil. Signal to noise ratio (SNR), sodium concentration ([ 23 Na]) and cortico-medullary sodium gradient (CMSG) were measured. Reproducibility of [ 23 Na] measurement was also tested. SNR, [ 23 Na] and CMSG of the native and transplanted kidneys were compared. Results Proton and sodium images of kidneys were successfully acquired. SNR and [ 23 Na] measurements of the native kidneys were reproducible at two different sessions. [ 23 Na] and CMSG of the transplanted kidneys was significantly lower than those of the native kidneys: 153.5 ± 11.9 vs. 192.9 ± 9.6 mM ( P  = 0.002) and 8.9 ± 1.5 vs. 10.5 ± 0.9 mM/mm ( P  = 0.041), respectively. [ 23 Na] and CMSG of the transplanted kidneys with normal function vs. acute rejection were not statistically different. Conclusions Sodium quantification of kidneys was reliably performed using proton/sodium MRI. [ 23 Na] and CMSG of the transplanted kidneys were lower than those of the native kidneys, but without a statistically significant difference between patients with or without renal allograft rejection. Key Points • Dual-tuned proton/sodium RF coil enables co-registered proton and sodium MRI . • Structural and sodium biochemical property can be acquired by dual-tuned proton/sodium MRI . • Sodium and sodium gradient of kidneys can be measured by dual-tuned MRI . • Sodium concentration was lower in transplanted kidneys than in native kidneys . • Sodium gradient of transplanted kidneys was lower than for native kidneys .

Idiopathic calcium oxalate (CaOx) stones often develop attached to Randall’s plaque present on kidney papillary surfaces. Similar to the plaques formed during vascular calcification, Randall’s plaques consist of calcium phosphate crystals mixed with an organic matrix that is rich in proteins, such as inter-α-trypsin inhibitor, as well as lipids, and includes membrane-bound vesicles or exosomes, collagen fibres and other components of the extracellular matrix. Kidney tissue surrounding Randall’s plaques is associated with the presence of classically activated, pro-inflammatory macrophages (also termed M1) and downregulation of alternatively activated, anti-inflammatory macrophages (also termed M2). In animal models, crystal deposition in the kidneys has been associated with the production of reactive oxygen species, inflammasome activation and increased expression of molecules implicated in the inflammatory cascade, including osteopontin, matrix Gla protein and fetuin A (also known as α2-HS-glycoprotein). Many of these molecules, including osteopontin and matrix Gla protein, are well known inhibitors of vascular calcification. We propose that conditions of urine supersaturation promote kidney damage by inducing the production of reactive oxygen species and oxidative stress, and that the ensuing inflammatory immune response promotes Randall’s plaque initiation and calcium stone formation.Calcium oxalate kidney stones are often found attached to Randall’s plaques in the kidney papilla. Here, the authors examine the mechanisms underlying the formation of Randall’s plaques, including the role of mineralization modulators, as well as inflammation and immune cells.

The renal medullary region is particularly vulnerable to reduced oxygen concentration because of its low blood perfusion and high basal oxygen consumption. This study investigated renal metabolic changes in relation to the previously observed decreased oxygen tension in streptozotocin-induced diabetic rats. Blood perfusion, oxygen tension and consumption, interstitial pH, and glycolytic and purine-based metabolites were determined in the renal cortex and the medulla of non-diabetic and diabetic animals by, respectively, laser Doppler flowmetry, oxygen and pH microelectrodes, and microdialysis. The importance of increased polyol pathway activity for the observed alterations was investigated by daily treatment with the aldose reductase inhibitor AL-1576 throughout the course of diabetes. The diabetes-induced decrease in renal oxygen tension, due to augmented oxygen consumption, did not result in manifest hypoxia in either the cortical or the medullary region, as evaluated by microdialysis measurements of purine-based metabolites. The profound alterations in medullary oxygen metabolism were, however, associated with an increased lactate : pyruvate ratio and a concomitantly decreased pH. Notably, the renal medullary changes in oxygen tension, oxygen consumption, lactate : pyruvate ratio and pH were preventable by inhibition of aldose reductase. Substantial metabolic changes were observed in the renal medulla in diabetic animals. These disturbances seemed to be mediated by increased polyol pathway activity and could be prevented by inhibition of aldose reductase.

Kidney stone disease causes significant morbidity and increases health care utilization. In this work, we decipher the cellular and molecular niche of the human renal papilla in patients with calcium oxalate (CaOx) stone disease and healthy subjects. In addition to identifying cell types important in papillary physiology, we characterize collecting duct cell subtypes and an undifferentiated epithelial cell type that was more prevalent in stone patients. Despite the focal nature of mineral deposition in nephrolithiasis, we uncover a global injury signature characterized by immune activation, oxidative stress and extracellular matrix remodeling. We also identify the association of MMP7 and MMP9 expression with stone disease and mineral deposition, respectively. MMP7 and MMP9 are significantly increased in the urine of patients with CaOx stone disease, and their levels correlate with disease activity. Our results define the spatial molecular landscape and specific pathways contributing to stone-mediated injury in the human papilla and identify associated urinary biomarkers. Kidney stone disease causes significant morbidity and increases in health care utilization. Here, the authors define the spatial molecular landscape and specific pathways contributing to stone-mediated injury in the human renal papilla and identify associated urinary biomarkers.

Deposits of hydroxyapatite called Randall’s plaques are found in the renal papilla of calcium oxalate kidney stone formers and likely serve as the nidus for stone formation, but their pathogenesis is unknown. Claudin-2 is a paracellular ion channel that mediates calcium reabsorption in the renal proximal tubule. To investigate the role of renal claudin-2, we generated kidney tubule–specific claudin-2 conditional KO mice (KS-Cldn2 KO). KS-Cldn2 KO mice exhibited transient hypercalciuria in early life. Normalization of urine calcium was accompanied by a compensatory increase in expression and function of renal tubule calcium transporters, including in the thick ascending limb. Despite normocalciuria, KS-Cldn2 KO mice developed papillary hydroxyapatite deposits, beginning at 6 months of age, that resembled Randall’s plaques and tubule plugs. Bulk chemical tissue analysis and laser ablation–inductively coupled plasma mass spectrometry revealed a gradient of intrarenal calcium concentration along the corticomedullary axis in normal mice that was accentuated in KS-Cldn2 KO mice. Our findings provide evidence for the “vas washdown” hypothesis for Randall’s plaque formation and identify the corticomedullary calcium gradient as a potential target for therapies to prevent kidney stone disease.

Glyphosate (GP) and its derivatives are present in almost all environments and suspected to induce acute and chronic kidney injuries. This public health issue is relatively underexplored. We therefore conducted an investigation on rats and tubular HK2 cells cultured for 24 h to determine whether GP’s and Roundup’s® (RU) potential renal toxicity might be related to mitochondrial respiration impairment and the increased production of hydrogen peroxide (H2O2) in both the renal cortex and medulla (involved in filtration and reabsorption, respectively) using a high-resolution oxygraph (Oxygraph-2K, Oroboros instruments). GP alone decreased maximal uncoupled mitochondrial respiration in the medulla (−14.2%, p = 0.02). RU decreased mitochondrial respiratory chain complexes I and I + II and the maximal respiratory capacity both in the renal cortex (−13.5%, p = 0.04; −20.1%, p = 0.009; and −14.7%, p = 0.08, respectively) and in the medulla for OXPHOS I + II (80.82 ± 7.88 vs. 61.03 ± 7.67 pmol/(s·mL), −24.5%, p = 0.003). Similarly, in HK2 cells, the decrease in OXPHOS CI + II was greater after RU (65.87 ± 1.30 vs. 51.82 ± 3.50 pmol/(s·mL), −21.3%, p = 0.04) compared to GP. Increased H2O2 production was mainly observed after RU in the medulla (+14.3% in OXPHOS CI + II, p = 0.04) and in HK2 cells (+19% in OXPHOS CI + II, p = 0.02). In conclusion, although the medulla might be more prone to GP-related mitochondrial damage, RU toxicity was greater in both the renal cortex and medulla and in cultured tubular HK2 cells. Enhancing mitochondrial respiration and reducing oxidative stress might favor the prevention of or reduction in such worldwide-used herbicides’ deleterious effects on the kidneys.

Kidney stone, one of the oldest known diseases, has plagued humans for centuries, consistently imposing a heavy burden on patients and healthcare systems worldwide due to their high incidence and recurrence rates. Advancements in endoscopy, imaging, genetics, molecular biology and bioinformatics have led to a deeper and more comprehensive understanding of the mechanism behind nephrolithiasis. Kidney stone formation is a complex, multi‐step and long‐term process involving the transformation of stone‐forming salts from free ions into asymptomatic or symptomatic stones influenced by physical, chemical and biological factors. Among the various types of kidney stones observed in clinical practice, calcareous nephrolithiasis is currently the most common and exhibits the most intricate formation mechanism. Extensive research suggests that calcareous nephrolithiasis primarily originates from interstitial subepithelial calcified plaques and/or calcified blockages in the openings of collecting ducts. These calcified plaques and blockages eventually come into contact with urine in the renal pelvis, serving as a nidus for crystal formation and subsequent stone growth. Both pathways of stone formation share similar mechanisms, such as the drive of abnormal urine composition, involvement of oxidative stress and inflammation, and an imbalance of stone inhibitors and promoters. However, they also possess unique characteristics. Hence, this review aims to provide detailed description and present recent discoveries regarding the formation processes of calcareous nephrolithiasis from two distinct birthplaces: renal interstitium and tubule lumen.

Thallium (Tl) is one of the most toxic heavy metals, associated with accidental poisoning and homicide. It causes acute and chronic systemic diseases, including gastrointestinal and cardiovascular diseases and kidney failure. However, few studies have investigated the mechanism by which Tl induces acute kidney injury (AKI). This study investigated the toxic effects of Tl on the histology and function of rat kidneys using biochemical and histopathological assays after intraperitoneal thallium sulfate administration (30 mg/kg). Five days post-administration, rats exhibited severely compromised kidney function. Low-vacuum scanning electron microscopy revealed excessive calcium (Ca) deposition in the outer medulla of Tl-loaded rats, particularly in the medullary thick ascending limb (mTAL) of the loop of Henle. Tl accumulated in the mTAL, accompanied by mitochondrial dysfunction in this segment. Tl-loaded rats showed reduced expression of kidney transporters and channels responsible for Ca2+ reabsorption in the mTAL. Pre-administration of the Na–K–Cl cotransporter 2 (NKCC2) inhibitor furosemide alleviated Tl accumulation and mitochondrial abnormalities in the mTAL. These findings suggest that Tl nephrotoxicity is associated with preferential Tl reabsorption in the mTAL via NKCC2, leading to mTAL mitochondrial dysfunction and disrupted Ca2+ reabsorption, culminating in mTAL-predominant Ca crystal deposition and AKI. These findings on the mechanism of Tl nephrotoxicity may contribute to the development of novel therapeutic approaches to counter Tl poisoning. Moreover, the observation of characteristic Ca crystal deposition in the outer medulla provides new insights into diagnostic challenges in Tl intoxication.

Randall’s plaques (RP) are well established as precursor lesions of idiopathic calcium oxalate (CaOx) stones, and the process of biomineralization driven by osteogenic-like cells has been highlighted in RP formation, but the mechanism is poorly understood. Given the inhibitory role of α-Klotho (KL), an aging suppressor protein with high expression in kidneys, in ectopic calcification and the close association between KL gene polymorphisms and urolithiasis susceptibility, we determined the potential role of KL in RP formation. This study found that both soluble KL (s-KL) and transmembrane KL (m-KL) were downregulated, and that s-KL but not m-KL was inversely correlated with upregulation of osteogenic markers in RP tissues. Additionally, s-KL expression was markedly suppressed in human renal interstitial fibroblasts (hRIFs) and slightly suppressed in HK-2 cells after osteogenic induction, intriguingly, which was echoed to the greater osteogenic capability of hRIFs than HK-2 cells. Further investigations showed the inhibitory effect of s-KL on hRIF osteogenic differentiation in vitro and in vivo. Moreover, coculture with recombinant human KL (r-KL) or HK-2 cells suppressed osteogenic differentiation of hRIFs, and this effect was abolished by coculture with KL-silenced HK-2 cells or the β-catenin agonist SKL2001. Mechanistically, s-KL inactivated the Wnt–β-catenin pathway by directly binding to Wnt2 and upregulating SFRP1. Further investigations identified activation of the Wnt–β-catenin pathway and downregulation of SFRP1 and DKK1 in RP tissues. In summary, this study identified s-KL deficiency as a pathological feature of RP and revealed that s-KL released from HK-2 cells inhibited osteogenic differentiation of hRIFs by inactivating the Wnt–β-catenin pathway, not only providing in-depth insight into the role of s-KL in renal interstitial biomineralization but also shedding new light on the interaction of renal tubular epithelial cells with interstitial cells to clarify RP formation.

Endoscopic and biopsy findings have identified two distinct phenotypes among individuals with calcium oxalate (CaOx) kidney stones. The first type has normal renal papillae but shows interstitial mineral deposition, known as Randall's plaque. The other phenotype presents with collecting duct plugging and a higher incidence of loss of papilla tissue mass. With Randall’s plaque, renal papilla injury involves the loss of small patches of calcified tissue (Randall’s plaque detaching with the stone), which likely results in damage to only a few nephrons. In contrast, collecting duct mineral plugs are very large, causing obstruction to tubular flow. Since each terminal collecting duct drains thousands of nephrons, ductal plugs could lead to the degeneration of many nephrons and a significant loss of renal glomeruli. New visualization techniques for immune cells in papillary biopsies have revealed that the Randall's plaque phenotype is marked by the accumulation of macrophages around the plaque regions. In contrast, preliminary data on the plugging phenotype shows collecting duct damage with mineral plugs and increased T-lymphocytes throughout the papilla. These regions also show tubulitis, i.e., T-cell infiltration into nearby collecting duct epithelium. This suggests that while some CaOx stone formers may have some papillary inflammation but with minimal damage to nephrons, others suffer from obstruction to flow for many nephrons that may also include destructive inflammation in the renal tissue. We propose that CaOx stone formers with the plugging phenotype will have a higher long-term risk for loss of renal function.