Acute kidney injury

The prevalence of acute kidney injury (AKI) continues to increase, and with repeated injury, AKI is considered an important risk factor for the development of chronic kidney disease (CKD) [67].

Hypoxia, or inadequate tissue oxygenation, is one of the main causes of AKI. This condition is usually caused by cardiac and/or pulmonary disease and can be modeled in preclinical animal models by i /R injury. After i /R injury, reduced HA expression is associated with reduced inflammation and enhanced renal recovery. Although HA has been suggested to promote a pro-inflammatory environment in the aforementioned I/R models, the involvement of MW variants of HA in the progression of injury remains unclear. However, a similar study using the I/R injury model found that HMW-HA accumulated one day after injury but degraded into smaller fragments over time. These findings suggest that LMW-HA may be a mediator of the pro-inflammatory environment that leads to AKI. In support of this hypothesis, we have demonstrated that il -10-induced HMW-HA has cytoprotective and antifibrotic effects after I/R injury.

Kidney fibrosis and CKD

CKD disproportionately affects children because it is an incurable, lifelong disease. The etiology of pediatric CKD is markedly different from that of adults, with congenital renal and urinary tract abnormalities predominating in children under 12 years of age and glomerulonephritis in older children [68].

Repeated AKI often leads to sustained activation of fibroblasts and ultimately tubular interstitial fibrosis, an inevitable outcome of CKD. Han et al. reported increased expression of HA, CD44, and LYVE-1 in areas of fibrotic tissue and noted that the accumulation of HA was associated with increased α-SMA [69], resulting in a pro-inflammatory and fibrotic environment in animal models of CKD.

Although the ultimate outcome of CKD is interstitial fibrosis leading to renal failure, the identification of patients with progressive disease is challenging in the absence of high-risk biomarkers. Given the putative role of HA as a major mediator of fibrosis in patients with CKD, HA serum levels may help clinicians provide a more definitive diagnosis. a study by Akin et al. showed that mean serum levels of HA were significantly higher in patients with CKD than in patients with AKI. In addition, it was found that HA serum concentrations in the CKD group were selectively correlated with serum albumin concentrations and proteinuria [70]. These results suggest that serum HA concentration can be used as a biomarker to differentiate CKD from AKI in uremic patients with unknown renal function.

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One of the most important effects of Cistanche on the kidneys is its ability to improve kidney function. In several studies, patients with kidney disease were given Cistanche supplements. The results showed that Cistanche helped reduce inflammation, improve blood flow to the kidneys, and increase the excretion of waste products from the body.

Obstructive uropathy

Human obstructive uropathy is a common condition usually caused by kidney stones, infection, blood clots, or tumors. A study found similar changes in hemagglutinin levels between obstructed and normal kidneys, due to uninjured kidneys compensating for the unmet hemagglutinin needs of damaged kidneys. Interstitial HA levels were elevated after obstruction due to stimulation of HA synthesis by papillary mesenchymal cells [71].

Similar to its role in AKI, HMW-HA helps to attenuate fibrosis after obstruction [22], suggesting that HA MW may play an ameliorative role in the disease. In our recent publication, we found that HMW-HA was significantly increased in the interstitium immediately after UUO onset, peaking 3 days after induction, indicating an initial pro-regenerative and cytoprotective response to injury. However, over time, LMW-HA levels increased - likely due to uncontrolled inflammation and increased HYALs (Figure 2) - ultimately leading to fibrosis. A schematic diagram shows how HMW-HA attenuates UUO-induced interstitial fibrosis (Figure 3).

HA is particularly relevant to obstructive uropathy because it can form negatively charged gel-like matrices, conferring them the ability to bind crystals. It has been shown that HA is effective in preventing the precipitation of calcium salts from solution, and under physiological conditions, HA can bind multiple calcium carboxyl groups and prevent crystallization [72]. Conversely, other reports on the role of HA in kidney stone formation suggest that it actually acts as a binder for precipitated calcium salts in the renal medulla and cortex, which can eventually lead to Randall's plaque and renal calculus. Critically, however, none of these studies assessed the impact of the molecular weight of HA on the pathogenesis of obstruction.

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Diabetic nephropathy

Diabetic nephropathy is the leading cause of ckd5 worldwide and can affect patients with type I (T1D) or type II (T2D) diabetes [73,74]. Although T1D has traditionally been associated with children and adolescents and T2D with adults, the increase in childhood obesity has led to an increased incidence of T2D in the youth population [75]. In either case, HA has been consistently associated with the development of diabetic nephropathy in several in vitro studies in which elevated HA levels were found in animal models of diabetes. Although HA has been identified as a mediator of interstitial fibrosis, it does not indicate the actual progression of diabetic nephropathy despite its overexpression in the kidney [73].

One of the pathological processes leading to diabetic nephropathy is endothelial damage, in which HA is a key component of the glycocalyx layer and therefore could serve as a more sensitive biomarker for diabetic nephropathy. To determine the effect of endothelial HA deficiency on diabetic nephropathy, a study found that mice lacking endothelial HAS2 exhibited abnormal glomerular endothelial structure. Similarly, another study showed that HA levels in the kidneys of diabetic rats decreased at 8 weeks [76]. HA has also been tested as a treatment for diabetic nephropathy, as HMW-HA attenuated inflammation and glomerulosclerosis in T2D mice. Given that diabetic nephropathy is a progressive disease, early detection of the disease by assessing hemagglutinin levels may have diagnostic and prognostic benefits.

IgA nephropathy

IgA nephropathy (IgAN) is characterized by the accumulation of immunoglobulin A (IgA), an antibody that induces inflammation in the glomerulus. In severe cases, this inflammatory process can form an irreversible fibrotic crescent that eventually leads to CKD [77].

Binding to HA, bone-bridging proteins regulate leukocyte activation and migration upon binding to CD44, and bone-bridging proteins bind to the same receptor to promote cell migration and adhesion. Since the interaction of HA and OPN with CD44 is associated with crescent formation, a team of researchers investigated whether this interaction is related to the development of IgAN. Their study showed a correlation not only between HA/CD44 binding and IgAN but also between interstitial expression of bone-bridging proteins and CD44 and the degree of tubulointerstitial damage and chronic glomerular lesions. Subsequently, another group investigated the role of α-SMA as a crescent formation-associated protein in crescentic glomerulonephritis and found that α-SMA, CD44, HA, and bone-bridging protein levels were upregulated early in the disease. Furthermore, CD44-HA and cd44 -bone bridging protein complexes were found to promote cell-matrix and myofibroblast interactions, which may transduce key signals during crescent development.

These collective data suggest that interactions between α-SMA, CD44, HA, and bone bridge proteins play a role in the development of crescentic glomerulonephritis and that targeting HA-related effects can yield therapeutic benefits.

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Vesicoureteral reflux

Vesicoureteral reflux (VUR) is a condition occurring in approximately 1% of the pediatric population in which urine flows retrogradely from the bladder into the ureter and ultimately into the kidney [78]. VUR caused by incomplete closure of the valve at the vesicoureteral junction is classified as primary, or VUR caused by intravesical hypertension is classified as secondary [79].

HA has been tested as a therapeutic agent for this condition, and several clinical studies have shown that dextran/hyaluronic acid (Dx/HA) injection is a safe and effective treatment for patients with primary VUR. One study showed that Dx/HA copolymer reduced VUR-induced urinary tract infections (UTIs), and other similar studies have shown that VUR with pelvic ureteral junction obstruction has a resolution success rate of nearly 85% [80]. Since VUR is also closely associated with renal fibrosis, other studies have shown that endoscopic treatment with Dx/HA is effective in reducing fibrosis [81]. In addition, the incidence of urinary tract infection after open surgery is 2 - 5 times higher than with Dx/HA treatment, depending on the concomitant fever [82]. The efficacy of HA-based therapy in VUR highlights its safety and sets a precedent for the potential benefits of HA in other renal diseases.

Conclusion

Understanding the double-edged nature of the HA MW variant provides insight into the seemingly contradictory roles of HA in vivo. Even HMW-HA, which is known to have anti-inflammatory/fibrotic effects, can become detrimental if broken down into shorter oligosaccharide or LMW variants. These size variants and their corresponding interactions with cofactors such as HAS, HYAL, HA receptors, and binding proteins suggest that HA is part of a highly subtle signaling pathway in various renal diseases. Indeed, in the context of the HAS/HA/CD44 signaling complex, the conversion of HA from high to low molecular weight has been found to mediate tumor progression, thus providing a promising therapeutic target for kidney cancer research [83]. In addition, HA could serve as a potential biomarker, as growth factors and cytokines are observed to be upregulated in HA in transplant rejection. This leads to the accumulation of HA in the renal cortex and sclerotic vessels, instead of its normal presence in the medulla under physiological conditions [84,85]. These promising clinical applications highlight the need to further investigate HA and its accessory molecules, especially in the context of their molecular weight. As researchers uncover the greater complexity of HA signaling mechanisms, these insights may be used to improve the prognosis of pediatric patients with various renal diseases.

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Aditya Kaul¹ ; Kavya L. Singampalli^1,2,3 ; Umang M. Parikh¹ ; Ling Yu¹ ; Sundeep G. Keswani¹ ; Xinyi Wang¹

1 Laboratory for Regenerative Tissue Repair, Division of Pediatric Surgery, Department of Surgery, Texas Children’s Hospital/Baylor College of Medicine, Houston, TX 77030, USA

2 Medical Scientist Training Program, Baylor College of Medicine, Houston 77030, TX, USA

3 Department of Bioengineering, Rice University, Houston 77030, TX, USA