Proteinuria is a common clinical manifestation in the majority of patients with chronic kidney disease (CKD). Recent evidence from a large number of clinical studies indicates that the degree of proteinuria is closely related to the prognosis of kidney disease, and therefore controlling proteinuria has become an important target for the treatment of CKD. The production of proteinuria is both a consequence of glomerular lesions and a key factor in tubulointerstitial damage and in promoting the chronic progression of renal lesions. Proteinuria has been a hot spot for research on its damaging effects on the tubulointerstitium, and there are several theories. A. Direct toxicity theory Early experiments have confirmed that urinary protein has a direct toxic effect on renal tubular cells. In vitro cultured proximal tubular epithelial cells with plasma proteins such as albumin, IgG, and transferrin have significantly increased the expression level of endothelin-1, which not only constricts blood vessels, but also is an important mediator that stimulates the proliferation of renal intrinsic cells, synthesizes extracellular matrix, and leads to monocyte chemotaxis. In recent years, the direct toxic effects of albumin on renal tubules have also been challenged. caruso-Neves et al. found that small amounts of albumin promote the growth of renal tubular epithelial cells, whereas large amounts of albumin lead to apoptosis of renal tubular epithelial cells. It has been shown that small molecules bound to albumin such as free fatty acids, transferrin, and hemiantigens play an important role in the development of tubular inflammation, in which albumin plays only a carrier role. Of all the protein components that are filtered from the glomerulus into the tubular fluid, who exactly is the kind of protein that exerts a toxic effect and the direct toxic effect of the albumin in question deserve further study. Second, the complement activation theory Complement activation has been an important pathway involved in the inflammatory response. In vitro experiments revealed that the expression level of complement C3 gene and protein increased after co-culture of albumin with proximal renal tubular epithelial cells. In vivo experiments also confirmed that complement C3 synthesis was increased and activated in renal tubular epithelial cells during proteinuria, playing an important role in the interstitial inflammatory response. Meanwhile, Abbate et al. found that after severe disruption of the glomerular filtration membrane barrier, serum macromolecules such as complement C3 are filtered out along with albumin, forming a membrane attack complex locally in the tubular epithelium, releasing inflammatory mediators, which cause a more intense inflammatory response than that caused by complement synthesized locally in the renal tissue. The role of complement in the tubulointerstitial inflammatory response is further confirmed by the inhibition of the tubulointerstitial inflammatory response by complement inhibitors given in the presence of proteinuria. The difference in the role of circulating complement and local interstitial complement activation in the tubulointerstitial response needs to be further elucidated. The superoxide overproduction theory is a common pathogenesis of many diseases. It has been shown that HK-2 cells cultured with albumin or IgG produce the second messenger ROS, leading to H2O2 production, which increases NF-ΚB activity and produces inflammation, and that antioxidant treatment inhibits NF-ΚB activity. Specific PKC inhibitors inhibit H2O2 production and thus NF-ΚB activity, demonstrating the involvement of excessive superoxide production in the development of tubulointerstitial inflammation. However, in addition to excessive superoxide production that activates NF-ΚB, other cytokines can also activate NF-ΚB, and apparently the protein has other toxic effects. nakajima et al. found that albumin activated the STAT signaling pathway in renal tubular epithelial cells, producing ROS and causing renal tissue damage, and also found that abnormal clearance of ROS also led to tubulointerstitial inflammation. Elucidating the balance between ROS production and clearance can better identify the toxic effects of proteinuria. Studies have shown that albumin acts with renal tubular epithelial cells to produce a series of pro-inflammatory and fibrotic factors, causing tubulointerstitial inflammation. In an experimental rat nephropathy model, proteinuria induced high expression of MCP-1 and osteopontin in renal tubular epithelial cells, as well as upregulation of nuclear transcription factor NF-κB activity and inflammatory response in the tubulointerstitium. Clinical studies have shown that renal tissue MCP-1 expression in CKD patients is positively correlated with proteinuria levels, which mediates mononuclear macrophage infiltration. TGF-β1 plays a crucial role in this process by inducing Smad2 phosphorylation in renal tubular epithelial cells, while BMP-7 inhibits TGF-β1-induced EMT. Proximal tubular The megalin and cublin receptors on the epithelial cells not only mediate albumin reabsorption, but also, both receptors are directly involved in the toxic effects of proteinuria. Among them, the megalin receptor has the properties of a signaling molecule that regulates cellular signaling pathways after protein uptake, promoting transcription of growth factor receptors and the release of inflammatory mediators. The mechanism of action of proximal renal tubular epithelial cells in processing albumin is complex, and further elucidation of the structure of megalin and its interaction with other receptors could help to elucidate the nephrotoxic effects of proteinuria. V. Immune-mediated theory Under physiological conditions, the proximal tubule plays a very important role in the reabsorption and degradation of protein. The urinary protein filtered into the proximal tubule is actively reabsorbed into the blood through catabolism into amino acids for reuse by the body, while the other part of urinary protein is degraded into peptide fragments mainly through receptor-dependent pathways, of which the immunogenic peptide fragments are degraded through dendritic cells (DCs) by epitope spreading and cross-presentation. The immunogenic peptide fragments are presented to lymphocytes through dendritic cells (DCs) by epitope spreading and cross-presentation, indirectly causing renal inflammation. This demonstrates that immune factors play a crucial role in proteinuric nephrotoxicity. These studies demonstrate the interconnection between the glomerular and tubular interstitium in the progression of CKD, with immunogenic protein fragments being trapped by perinephric DCs, presenting antigens to CD8+ cells, promoting the production of various cytokines and chemokines, and leading to infiltration of renal interstitial inflammatory cells. The activated CD8+ cells further promote the release of glomerular antigens, which are presented to CD8+ cells by DCs cells. This cross-talk between DCs cells and CD8+ cells results in a positive feedback loop between the two, leading to continuous inflammation. The presentation of antigenically active protein fragments from perinephric DCs cells to Th cells may be one of the novel mechanisms leading to monocyte infiltration. Accordingly, Sungs et al. proposed the hypothesis of a glomerular feedback mechanism linking glomerular injury, proteinuria, epitope expansion, and tubulointerstitial inflammation. After glomerular injury, urinary protein is filtered out and broken down into antigenically active fragments in the tubulointerstitium, which are presented to CD8+ cells via DCs cells, which in turn can trigger glomerular feedback and further promote glomerular antigen release, causing increased acute inflammation and progression of CKD, and even if the primary etiology is controlled, the delayed hypersensitivity response can still lead to renal tissue injury. But through which cytokines or inflammatory mediators do CD8+ cells cause glomerular antigen release? And how do inflammatory mediators interact with podocytes? Can these inflammatory mediators activate the local RAS system in the kidney? These are still not well understood and need to be further investigated. In conclusion, there are various pathways of toxic effects caused by proteinuria, and a better understanding and elucidation of how urinary protein promotes inflammation and leads to the persistence of inflammation can provide a better means to reverse renal fibrosis and prevent CKD. At the same time, the combination of multiple drugs to reduce urinary protein and the combination of treatments targeting each damage pathway can help reduce its nephrotoxicity and slow down the progression of CKD.