Oxalate Nephropathy and the Mechanism of Oxalate-Induced Kidney Injury

Abstract

Background

Hyperoxaluria is a major cause of oxalate nephropathy, which can lead to impaired renal function presenting as acute kidney injury, acute on chronic kidney disease, or chronic kidney disease. The Chronic Renal Insufficiency Cohort study showed that higher urinary oxalate is associated with renal outcome in patients with chronic kidney disease, supporting the nephrotoxicity of oxalate. Therefore, a better understanding of the role of oxalate in kidney injury is needed. This review describes the metabolism of oxalate and the clinical and pathology presentation of oxalate nephropathy. It also summarizes the available evidence for the underlying pathogenic mechanism and the development of treatments for oxalate-induced kidney injury.

Summary

Disruption to any key step in the oxalate pathway including abnormal endogenous generation, ingestion of abnormally high dose of oxalate, increased absorption or attenuation of oxalate degradation in the gut, and reduced excretion through the kidney may lead to disrupted oxalate homeostasis. Oxalate nephropathy is mainly caused by hyperoxaluria. Oxalate crystal deposition in the kidney is usually accompanied with tubular toxicity, obstruction, interstitial fibrosis, and tubular atrophy. The mechanism of oxalate-induced renal injury has not been fully clarified. Evidence from both in vivo and in vitro studies shows that NLRP3 inflammasome activation and macrophage infiltration are involved in the processes of crystal adhesion, aggregation, and elimination and promote intrarenal inflammation and renal fibrosis. Novel treatment strategies have been developed and targeted therapies tested for oxalate nephropathy.

Key Messages

Prompt diagnosis and management may help to reduce the deposition of calcium oxalate crystals in the kidney. Further studies are needed to clarify the underlying mechanisms to help develop more targeted therapies for oxalate nephropathy.

Introduction

Oxalate nephropathy is defined as kidney injury induced by calcium oxalate (CaOx) crystal deposition in kidney tissues resulting in impaired renal function, which may present as acute kidney injury (AKI), chronic kidney disease (CKD), or even end-stage renal disease (ESRD) [1, 2]. Oxalate nephropathy in most cases results from hyperoxaluria, which may be classified into primary and secondary or enteric hyperoxaluria [3–5]. The exact prevalence of oxalate nephropathy is unknown; however, the prognosis of oxalate nephropathy is poor. Although recent results from in vitro and in vivo studies have indicated that inflammasome activation plays a critical role in oxalate-induced kidney injury, a better understanding of the metabolism and pathogenic role of oxalate will help the development of interventions to alleviate progressive kidney damage in oxalate nephropathy. This review mainly focuses on the clinical features, the mechanism of oxalate-induced kidney injury, and the management of oxalate nephropathy, with the aim to raise awareness of the relationship between oxalate and kidney injury.

Oxalate Metabolism

Oxalate homeostasis is a complex process involving supply, metabolism, and excretion (Fig. 1). Exogenous dietary oxalate was believed to have a minor contribution to urine oxalate excretion, of between 10 and 20% [6]. However, evidence indicates that dietary oxalate may contribute up to 80% of oxalate excreted in urine [7]. This level of variation is associated with several factors, including dietary calcium intake, absorption from the gut, intestinal bacteria, and bioavailability of oxalate. Certain foods, such as fruit juice, leafy greens, especially spinach, nuts, and tea, have large amounts of oxalate and oxalate precursors, like vitamin C [2, 6, 8]. These are absorbed into the enterohepatic circulation, then absorbed along the intestinal tract via transcellular anion transporters, and secreted via the solute-linked carrier (SLC)-26 family. SLC26A6 null mice have elevated plasma oxalate, higher urinary oxalate excretion, and a greater risk of nephrolithiasis [9, 10]. Dietary oxalate intake maintained at 100–200 mg per day is thought to be a safe level [11]. Only about 15% of dietary oxalate is absorbed in the gut; most is prevented from doing so by binding with calcium or being degraded by intestinal bacteria, such as Oxalobacter formigenes [12, 13].

Fig. 1.

Physiological oxalate homeostasis.

The liver is the primary source of endogenous oxalate, which is synthesized from the precursor glyoxylate, and contributes to 60–80% of plasma oxalate [12, 14]. The mechanism of oxalogenesis is incompletely understood, but many pathways produce glyoxylate by conversion of hydroxyproline, glycolate, glycine, and other amino acids, such as tryptophan, tyrosine, and phenylalanine. In a physiologically balanced state, glyoxylate is converted to glycine by peroxisomal alanine-glyoxylate aminotransferase (AGT) in liver cells, or retransformed into glycolate through cytosol glyoxylate reductase-hydroxypyruvate reductase (GRHPR), or converted to oxalate by liver-specific lactate dehydrogenase A (LDHA) [12, 15]. The other possible pathway of oxalate generation is degradation of vitamin C, also called ascorbic acid, which is broken down to 2,3-diketogulonic acid in a nonenzyme step. 2,3-Diketogulonic acid can then be split into threosone or erythrulose, accompanied by oxalate in both cases [6]. Several large cohort studies have revealed the association between ascorbic acid intake and urinary oxalate excretion or risk of kidney stone formation. Ferraro et al. [16] revealed that total and supplemental intake of vitamin C was significantly associated with a higher risk of kidney stones in men but not in women. Taylor et al. [17] also suggested that vitamin C intake promotes urinary oxalate excretion. A randomized cross-over trial demonstrated that 1,000 mg of supplemental vitamin C consumed twice daily increased urinary oxalate excretion by 22% [18]. These results indicate that vitamin C intake is an important determinant of urinary oxalate excretion in healthy individuals.

Oxalate either produced endogenously or absorbed from food is mainly excreted through the kidney as urinary oxalate. Oxalate excretion in urine is determined by glomerular filtration, tubular reabsorption, and active secretion in the proximal tubule [15]. The SLC-26 family mainly mediates oxalate transport in this process by anion exchange. Dysfunction of any key step in oxalate homeostasis can lead to disequilibrium. Such dysfunction may include (i) abnormal endogenous generation and transport associated with a genetic disorder, (ii) enhancement of intestinal absorption associated with dietary intake, reduced intestinal O. formigenes, or bowel disease [1, 2, 19, 20], and (iii) reduction of urinary excretion related to kidney disease. If plasma levels of oxalate rise, oxalate is deposited in all tissues (systemic oxalosis), including the skeleton, retina, cardiovascular system, and kidney [3, 21]. Oxalate is an ionized conjugate base and binds easily with calcium in the kidney; therefore, hyperoxaluria leads to urinary CaOx supersaturation, resulting in the formation of calcium oxalate crystals in renal tissue [21]. Hyperoxaluria is defined as urinary excretion of oxalate over 40–45 mg/day (0.45–0.5 mmol/day). Based on dysfunction in key steps of oxalate homeostasis, hyperoxaluria can generally be divided into two categories, primary and secondary hyperoxaluria.

Primary Hyperoxaluria

Primary hyperoxaluria (PH) is a group of autosomal recessive disorders involving the hepatic overproduction of oxalate. They are classified as PH type 1, 2, and 3 according to variations in alanine-glyoxylate aminotransferase (AGT), glyoxylate reductase-hydroxypyruvate reductase (GRHPR), and 4-hydroxy-2-oxoglutarate aldolase (HOGA) deficiencies [3]. These disorders tend to present in early childhood to adulthood, with deposition of oxalate that can occur in the kidneys, skin, retina, bone, and the cardiovascular and central nervous systems. Patients can also be asymptomatic, especially for PH 3 [1]. CaOx crystals, nephrocalcinosis, and subsequent nephrolithiasis deposits in renal parenchyma are thought to drive a decrease in estimated glomerular filtration rate, which leads to plasma oxalate elevation. This, in turn, initiates a vicious cycle; decreased estimated glomerular filtration rate results in reduced oxalate excretion, leading to CKD progression and ESRD [12, 21–23].

PH 1 is the most severe type, accounting for 70–80% of all cases, with a prevalence of 1–3 cases per million people [21, 22]. The median age for diagnosis is 6 years in patients retaining kidney function, but some patients are already in end-stage renal failure at the time of diagnosis [24]. PH 2 is caused by a lack of GPHPR and accounts for 7.9–10% of cases. It is characterized by accumulation of glyoxylate, which is converted to oxalate through LDHA in the liver, and hydroxypyruvate, which is converted to l-glycerate. Although PH 2 and PH 1 have similar clinical courses, that of PH 2 is less severe with stone formation and preserved kidney function. Urinary oxalate excretion is also higher in PH 1 (2.14 ± 1.29 mmol/1.73 m²/day) than in PH 2 (1.46 ± 0.49 mmol/1.73 m²/day) [25]. PH 3 has the least severe course and may be asymptomatic or limited to recurrent stone formation and sometimes improves over time [26, 27].

Secondary Hyperoxaluria

Secondary hyperoxaluria is more common than PH and may be associated with a number of different causes, including increased dietary oxalate intake, increased intestinal oxalate availability, decreased intestinal oxalate degradation, or increased colonic permeability to oxalate [20]. Certain foods, such as fruit juice, leafy greens, especially spinach, nuts, and tea, contain large amounts of oxalate and oxalate precursors, such as vitamin C, which are absorbed into the enterohepatic circulation and metabolized by O. formigenes in the gut [8, 28–31]. Renal failure after over-ingestion of starfruit has been reported and was confirmed as acute oxalate nephropathy [32, 33]. There have also been multiple case reports of oxalate nephropathy associated with the ingestion of vitamin C [8, 34].

A second pathway leading to increased oxalate absorption by the intestine is associated with fat malabsorption [1, 19]. Normally, oxalate combines with calcium to form insoluble calcium oxalate, which is excreted in the feces. Under conditions of fat malabsorption and steatorrhea, including short-bowel syndrome, gastric surgery (Roux-en-Y gastric bypass), usage of orlistat, and inflammatory bowel disease, calcium binds to free fatty acids, leading to increased free oxalate in the intestines [20]. Oxalate nephropathy is also an uncommon complication in patients with chronic pancreatitis or pancreatic insufficiency that may result from maldigestion [5].

Obesity is also associated with calcium oxalate nephrolithiasis. Taylor and Curhan [35] found participants with higher BMI excreted more urinary oxalate compared with participants with a lower BMI. Ekeruo et al. [36] also reported a greater prevalence of hyperoxaluria in an obese population of kidney stone formers compared with a nonobese population. Amin and colleagues found evidence in an obese mouse model to support obesity-associated hyperoxaluria as being enteric hyperoxaluria, which is pro-inflammatory cytokines that reduce active transcellular intestinal oxalate secretion. They also found lower SLC26A6 mRNA and protein levels in obese mice relative to controls, confirming SLC26A6 to play a crucial role in intestinal oxalate secretion in obese mice [37, 38].

Oxalate is metabolized in the gastrointestinal tract by O. formigenes, a Gram-negative obligate anaerobic bacterium that colonizes the colon. O. formigenes takes up oxalate through an oxalate-formate-antiport carrier and metabolizes it to formate and CO₂ for exclusive energy supply [31]. Low Oxalobacter counts after administration of antibiotics including macrolides, tetracyclines, metronidazole, and clindamycin can also increase oxalate absorption [30, 39, 40]. In irritable bowel disease, which carries a risk of enteric hyperoxaluria, impaired metabolic activity of the microbiota is correlated with enteric oxalate levels [40]. This provides strong evidence for O. formigenes restoration therapy. A recent study performed in a surgery-induced enteric hyperoxaluric rat model via Roux-en-Y gastric bypass indicated that O. formigenes achieved 100% colonization and that urinary oxalate was decreased by 74% in the post-Roux-en-Y gastric bypass rat compared with 39% in the sham-operated group [41]. This indicates the potential of O. formigenes for treating enteric hyperoxaluria. Several studies have investigated the prevalence and abundance of O. formigenes in humans. O. formigenes colonization was much lower in the US cohort compared with that in other populations [42, 43]. Furthermore, Clemente et al. [44] found that westernization significantly affects O. formigenes colonization independently of antibiotic exposure. This indicates that our modern lifestyle induces the disappearance of beneficial microbacteria.

Multiple studies have illustrated that urine excretion of oxalate is higher in individuals with diabetes mellitus compared with those without [14, 45]. A recent clinical trial (Chronic Renal Insufficiency Cohort study, CRIC study) conducted by Waikar and colleagues, which contained 3,123 individuals with established CKD, found that diabetes mellitus was independently associated with higher urinary oxalate excretion [46]. A possible explanation for this is that undetectable pancreatic exocrine insufficiency may exist in those diabetic patients [47]. In addition, increased generation of endogenous oxalate precursors, such as glyoxylate and glyoxal, in diabetes has been hypothesized [48–50]. Furthermore, in a mouse model of diabetes (C57BLKS/JLepr^−/−), glyoxylate levels were six-fold higher in diabetic mice than in control mice [49], supporting the above hypothesis.

Oxalate Nephropathy and Kidney Injury

Oxalate crystals are usually associated with tubular toxicity, obstruction, interstitial fibrosis, and tubular atrophy, affect renal function, and contribute to the development of AKI and/or CKD [1, 14, 48]. Furthermore, the CRIC study revealed that higher urine oxalate excretion is an independent risk factor for CKD progression and ESRD [46]. Under light microscopy, calcium oxalate crystals are gray white and spiculate in appearance [5]. They are birefringent under polarized light and are usually deposited in renal epithelial cells or renal tubules [1, 51] (Fig. 2).

Fig. 2.

Kidney biopsy sample of oxalate nephropathy. a Intratubular translucent polyhedral calcium oxalate crystals (black arrows) on light microscopy (hematoxylin and eosin stain, original magnification, ×200). b Calcium oxalate crystals are shown as birefringent under polarized light (white arrows) (original magnification, ×200).

Mechanism of Oxalate Deposition in the Kidney

The mechanism of oxalate deposition in the kidney is subject to several factors. These include supersaturation and precipitation, crystal aggregation, and deposition within the tubule/epithelium/interstitium [1]. In tubular fluid and urine, crystallization processes are largely dependent on solution composition. Several factors are usually protective against crystallization, such as a decline in urinary calcium. However, lower levels of urinary citrate and magnesium favor crystallization. The net effect of this usually depends on urinary supersaturation [52]. Urinary supersaturation is the driving force behind crystal formation in the kidneys. Even a small increase in urinary oxalate has a significant impact on calcium oxalate saturation, which can lead to calcium oxalate crystal formation, obstruction, and direct injury to tubular epithelial cells [1, 14, 53]. Persistent mild supersaturation also fosters a chronic dynamic of crystal formation, resulting in CKD [54]. The pH of urine also affects supersaturation. It has been suggested that metabolic acidosis provides favorable conditions for oxalate accumulation and precipitation in renal tissue [4]. Humans normally excrete millions of urinary crystals daily. Generally, the growth rate of CaOx crystals is 1-2 μm/min, while the diameter of renal tubule segments ranges from 15 to 60 µm and the transit time of urine across the kidney is approximately 5–10 min. The residence time is, therefore, too short for crystals to nucleate and grow large enough to be trapped in a normal person and they are excreted in urine without causing stone formation [55, 56]. It should be noted that factors affecting urine flow may provide favorable conditions for oxalate accumulation and precipitation. Diarrhea and vomit-induced dehydration are associated with insufficient renal perfusion, and decreased urine output with severe supersaturation promotes a sudden onset of crystal formation, renal epithelial cell damage, inflammation, and necrosis, leading to AKI [57]. Renin-angiotensin-aldosterone system inhibitor is commonly used in patients who are diagnosed with acute oxalate nephropathy [5], which may favor oxalate crystal-associated kidney injury through decreased glomerular filtration rate leading to insufficient renal perfusion [2]. In addition to being located in the collecting ducts, the degree of calcium oxalate adhesion also plays an important role in crystal-induced renal epithelium injury. Prostaglandins may decrease calcium oxalate adhesion to renal epithelial cells [58, 59]. Nonsteroidal anti-inflammatory drugs downregulate prostaglandin production; therefore, it is feasible that Nonsteroidal anti-inflammatory drugs predispose to a greater likelihood of stone formation [60]. Furthermore, proteins such as osteopontin are also constantly embedded in the interstitium in the CaOx formation progress, which binds to CD44, a membrane-bound glycoprotein on proximal renal tubular epithelial cells. Exposure to high levels of CaOx crystals upregulates the expression of CD44 through activation of the tumor necrosis factor (TNF) pathway. In TNF receptor-deficient mice, CaOx crystal deposition did not occur despite hyperoxaluria [61].

Oxalate-Induced Inflammasome Activation

Studies exploring the mechanism of oxalate-induced kidney injury have been mainly performed in vitro and in animal models. Accumulated evidence confirms calcium oxalate crystal deposition to be associated with renal epithelial damage [1]. The inflammasome has recently been identified to play a critical role in oxalate deposition and oxalate-induced renal injury [14]. The major mechanism of oxalate-induced inflammasome activation in nephropathy involves a multiprotein oligomer consisting of three cytosolic proteins, Nod-like receptor protein 3 (NLRP3), apoptosis-associated spot-like protein, and caspase-1 [14, 54, 62, 63]. Calcium oxalate crystals, crystalline particles, or other damage-associated molecular patterns, which are likely to be released secondary to oxalate crystals, can directly activate the NLRP3 inflammasome complex and damage renal tubular epithelial cells. This damage releases ATP, indirectly activating the NLRP3 inflammasome and stimulating IL-1β secretion by dendritic cells, resulting in a renal inflammatory response and also inflammatory injury to tubular epithelial cells [64]. The generation of reactive oxygen species (ROS) also activates the NLRP3 inflammasome. The interaction of calcium oxalate crystals with cells can cause mitochondrial damage and increased NADPH oxidase activity, and then generate ROS subsequently, which in turn promotes NLRP3 inflammasome transcription and activation through the ROS dependent of NF-κB and autophagy signaling pathway [64]. The mechanisms of inflammasome activation include phagolysosomal rupture and subsequent cathepsin B release and potassium efflux [63]. Furthermore, activated caspase-1 cleaves gasdermin-D (GSDMD). N-terminal fragments of GSDMD were demonstrated to oligomerize and insert into the plasma membrane to mediate the rapid cell lysis and induce a highly pro-inflammatory form of cell death called “pyroptosis,” which is characterized by cell swelling and hyperpermeabilization of the plasma membrane, and release of cytoplasmic contents, including IL-1β and IL-18, triggering necroinflammation [63, 65, 66]. An in vitro study has shown CaOx crystal-inducing pyroptosis of renal tubular epithelial cells to be associated with elevated levels of cleaved caspase-1, GSDMD-N, IL-1β, and IL-18 [67]. NLRP3 inflammasome activation also initiates inflammation in dendritic cells by releasing IL-1β and IL-18. These mediators can act as pro-inflammatory activators, which in turn promote the adhesion, aggregation, and growth of crystals and result in renal inflammation and renal failure in clinical [14, 54, 62–64]. In addition, an in vitro study revealed that NLRP3 also promotes TGF-β receptor signaling in fibroblasts, contributing to renal fibrosis [68]. This effect is an inflammasome-independent function of NLRP3 and bypass IL-1β and IL-18 secretion, directly contributing to fibrosis. These findings indicate NLRP3 to be a potential therapeutic target for the treatment of oxalate-induced kidney injury.

Role of Macrophages in Oxalate-Induced Kidney Injury

In the cell-crystal inflammatory process, macrophages, important inflammatory cells with phagocytic function, participate in CaOx crystal formation in the kidney. The population of macrophages is classified into two types depending on their function: pro-inflammatory M1 and anti-inflammatory M2 macrophages [69]. M1-like macrophages promote inflammation in the kidney and worsen the function of the kidney, leading to CKD and fibrosis. However, M2-like macrophages have an anti-inflammatory function and tissue healing effect [70]. CaOx crystal deposition and subsequent elimination are regulated by macrophages, and migration of macrophages occurs concurrently with crystal formation before their disappearance [69, 70]. Using in vitro models, Taguchi et al. [70] showed that M2 macrophages have a significant ability to phagocytose CaOx monohydrate crystals and prevent crystal adherence to renal tubular cells, whereas M1 macrophages facilitated renal crystal formation. Kusmartsev et al. [71] demonstrated that human macrophages in vitro are capable of phagocytizing and degrading calcium oxalate crystals produced naturally in the kidney. Kidneys developing CaOx crystals express several pro-inflammatory cytokines, crystal-related molecules, including osteopontin, CD44, and MCP-1, and adhesion-related genes, such as C3, FN, and Vcam1. Taguchi and colleagues showed that the expression of crystal-related and adhesion-related genes was increased in hyperoxaluric mice that had substantial crystal deposits in the kidneys. The expression of these genes in tubular cells and the renal interstitial cells was increased by M1 treatment but decreased by M2 treatment [70]. Anders et al. [68] observed that in wild-type mice fed with a high oxalate diet, NLRP3 inhibition using the β-hydroxybutyrate led to a transition of macrophages from M1 type to M2 type, relieved renal inflammation, and diminished renal fibrosis. These results indicate that NLRP3 contributes to oxalate-associated renal fibrosis by mediating a shift in macrophage phenotype.

Therapies for Hyperoxaluria and Oxalate Nephropathy

Treatment of oxalate nephropathy remains largely empirical and should be initiated immediately including high fluid intake, a low-oxalate and low-fat diet, and supplements that could improve the solubility of oxalate, such as calcium, citrate, and sodium bicarbonate, aiming to decrease both plasma and urine oxalate concentration [12, 72, 73]. Pancreatic enzyme therapy, intensive therapy of inflammatory bowel disease, and avoiding abuse of orlistat could be considered depending on the underlying causes [5]. We have studied a case series of 6 patients diagnosed with secondary oxalate nephropathy. Four patients showed improvement in kidney function after active therapy including hydration, oral citrate supplements, and alkalization. Four of the patients with severely elevated serum creatinine levels were administered a course of corticosteroid treatment; however, the rate of kidney function recovery was equal between patients with and without corticosteroid treatment, indicating uncertain efficacy of the steroid therapy [73]. Overall, the prognosis for oxalate nephropathy is poor and 40–50% of patients reach kidney failure or are dialysis dependent at their last follow-up [2, 5, 20]. Pre-existing CKD seems to be a risk factor for worsening kidney outcomes.

Microbiota-Related Approaches

The role of microbiota in reducing urinary oxalate excretion has been extensively investigated in animal models recently. Sidhu et al. [74] showed that a diet-induced hyperoxaluric rat model achieved an obvious reduction in urinary oxalate excretion after probiotic administration of O. formigenes. Likewise, Hatch et al. [75] demonstrated that colonization of O. formigenes reduced both urinary and plasma oxalate levels in PH 1 mouse model. Moreover, Chen et al. [76] transfected mouse stem cells with Oxc and Frc genes into intestinal stem cell population, encoding the oxalate decarboxylase and the formyl Co-A transferase, and demonstrated a reduction in oxalate levels in the media. However, although O. formigenes is well tolerated and successfully delivered to the gastrointestinal tract in a human study through an oral application (OC5, lyophilized O. formigenes in enteric-coated capsules), the evidence is mixed regarding the effectiveness of OC5 as a PH 1 treatment [77, 78]. Besides, colonization with Bifidobacterium and Lactobacillus species is also reported to decrease urinary oxalate excretion in a mouse model of PH [79]. These probiotic treatments appear to be safe and well tolerated. But determining their clinical benefit still requires long-term follow-up studies.

Treatments for PH

Conservative therapy aims to reduce the precipitation of calcium oxalate in the kidney. Hydration, urine alkalization, and pyridoxine supplements are adopted in clinical practice. Historically, kidney and liver transplantation has been the only effective option for ESRD patients. There are no approved drugs for all three types of PH. Novel promising therapeutic agents show promise at influencing the outcome of PH 1 patients. Lumasiran, an RNA interference that blocks the synthesis of enzyme and precursor of oxalate, has been confirmed to reduce plasma oxalate substantially in patients with advanced PH 1 with acceptable safety in a phase 3 ILLUMINATE-C Trial [80]. Lumasiran has recently been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency for the treatment of children and adults with PH 1. Nedosiran, another RNA interference targeting for inhibiting expression of hepatic lactate dehydrogenase, significantly reduced urinary oxalate excretion and persisted in the normal or near-normal range in most participants with PH 1 after 6 months of treatment in comparison with the placebo group in PHYOX2 [81]. As efficacy and safety of these emerging drugs are confirmed, liver transplantation may no longer be the only effective therapy for curing PH patients.

Immune Modulation Therapy

Current treatment options targeting inflammasome activation are directed against IL-1, principally through their central agent IL-1 receptor antagonist, anakinra. Anakinra has been approved by the FDA for the treatment of rheumatoid arthritis [82]. Mulay et al. [62] showed that injection of anakinra dose dependently reduced tubular injury and neutrophil recruitment and improved renal excretory function during oxalate nephropathy in rats. This supports blockade of IL-1 to protect from renal failure in oxalate nephropathy. Novel drugs targeting the NLRP3 inflammasome are being actively investigated. CP-456773, an NLRP3 inhibitor, suppresses the activation of NLRP3 inflammasome and diminished the expression fibrosis markers in mice fed with a higher oxalate diet, leading to less intrarenal inflammation and reduced renal fibrosis [83]. Another novel small molecule drug, OLT1177, inhibits the NLRP3 inflammasome specifically and reduces IL-1β and IL-18 release [84] and is safe and effective in patients with NLRP3 mutation-caused autoimmune disease [85].

Therapies focusing on regulating macrophage subtype transformation have also been developed because macrophages contribute to oxalate crystals-induced kidney injury. Peroxisome proliferator-activated receptor gamma (PPARγ) can directly upregulate the expression of microRNA-23, thereby reducing interferon regulatory factor 1 (Irf1) and PBX/knotted 1 homeobox 1 (Pknox1) expression, leading to conversion of M1-like macrophages to M2 macrophages [86]. Pioglitazone, a PPARγ activator, promotes the polarization of M2-like macrophages both in in vitro studies and in nephrocalcinosis mice and attenuates renal CaOx crystal deposition and renal injury [87]. This indicates a promising therapeutic target for oxalate nephropathy. We predict that with greater understanding of the oxalate-induced renal injury mechanism, more effective and more accurate therapeutic approaches will be developed.

Conclusion

Oxalate nephropathy is a rare but devastating cause of AKI, acute on CKD or CKD progression. The prognosis of the disease is poor, with a high rate of kidney failure. Prompt diagnosis and management may help to reduce oxalate absorption and deposition of calcium oxalate crystals in the kidney. Further studies are needed to clarify the pathogenic mechanisms of oxalate nephropathy. This will provide new avenues for targeted therapy and aid the development of new drugs for preventing or treating oxalate nephropathy in high-risk patients.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This work was supported by the National Natural Science Foundation of China (Nos. 81770671 and 82090021).

Author Contributions

Daorina Bao and Yu Wang were major contributors to the writing of the manuscript. Ming-Hui Zhao edited and revised the manuscript. All authors approved the final version.

Funding Statement

This work was supported by the National Natural Science Foundation of China (Nos. 81770671 and 82090021).