From Rare Disorders of Kidney Tubules to Acute Renal Injury: Progress and Prospective

Abstract

Background: Acute kidney injury (AKI) is a severe condition marked by rapid renal function deterioration and elevated mortality, with traditional biomarkers lacking sensitivity and specificity. Rare tubulointerstitial diseases encompass a spectrum of disorders, primarily including monogenic diseases, immune-related conditions, and drug-induced tubulointerstitial diseases. The clinical manifestations vary from electrolyte and acid-base imbalances to kidney function insufficiency, which is associated with AKI in up to 20% of cases. Evidence indicated that rare tubulointerstitial diseases might provide new conceptual insights and perspectives for novel biomarkers and potential therapeutic strategies for AKI.

Summary: Autosomal dominant tubulointerstitial kidney disease (ADTKD) and Fanconi syndrome (FS) are rare tubulointerstitial diseases. In ADTKD, UMOD and REN are closely related to AKI by affecting oxidative stress and tubuloglomerular feedback, which provide potential new biomarkers for AKI. Both rare tubulointerstitial diseases and AKI share etiologies and treatment responses. From the mechanism standpoint, rare tubulointerstitial diseases and AKI involve tubular transporter injury, initially manifesting as tubular dysfunction in tubulointerstitial disorder and progressing to AKI because of the programmed cell death with apoptosis, pyroptosis, or necroptosis of proximal tubule cells. Additionally, mitochondrial dysfunction has been identified as a common mechanism in both tubulointerstitial diseases and AKI induced by drugs, pSS, or monoclonal diseases. In the end, both AKI and FS patients and animal models responded well to the therapy of the primary diseases.

Key messages: In this review, we describe an overview of ADTKD and FS to identify their associations with AKI. Mitochondrial dysfunction contributes to rare tubulointerstitial diseases and AKI, which might provide a potential therapeutic target.

Keywords: Acute kidney injury; Mitochondrial disorder; Rare tubulointerstitial diseases.

Fig. 1.

Transporters in the PCT. The electrochemical gradient for passive entry of Na⁺ and other solutes via these transporters established by the basolateral Na⁺-K⁺-ATPase in PCT mediates the Na⁺ extrusion from the cytosol to the blood. NHE3 mediates the extrusion of H⁺ and reabsorption of Na⁺. Phosphate, glucose, amino acids, and lactate are reabsorbed into PCT via NaPi, SGLT1/2, Na⁺/amino acid, and Na⁺/lactate cotransporters. Citrate is reabsorbed via NaDC-1 and is then transported to the mitochondria for energy production. Cl⁻ can be reabsorbed through Cl⁻/oxalate and Cl⁻/formate exchangers and enter the blood via Cl⁻ channel, K⁺-Cl⁻ cotransport, and Na⁺-2HCO3⁻/Cl⁻ exchanger. HCO3⁻ is generated from glutamine in the cytosol and enters the bloodstream via the NBCe1. PCT, proximal convoluted tubule; NHE3, Na⁺-H⁺ exchanger; NaPi, Na⁺/phosphate cotransporter; SGLT2, Na⁺/glucose cotransporter 2; SGLT1, Na⁺/glucose cotransporter 1; GLUT2, glucose transporter 2; GLUT1, glucose transporter 1; NaDC-1, Na⁺/dicarboxylate cotransporter 1; NBCe1, Na⁺/HCO3⁻ cotransporter; ATPase, Na⁺-K⁺-ATPase.

Fig. 2.

The overall pathogenic mechanisms of FS. The etiologies of FS are primary and acquired mechanisms contributing to the dysfunction of PCT cells. The predominant mechanism is mitochondrial dysfunction secondary to mtDNA deletion, mitochondrial myopathies, tyrosinemia type 1, FRTS 1, 3, and 5, and heavy metal exposure, which impair the electron transport chain in mitochondria, resulting in reduced ATP production and accumulation of ROS. The second way is the deposition of Ig light chain or cystine crystal substances in MGRS and cystinosis, respectively. The other two mechanisms are direct cell damage or disruption of the cytoskeletal abnormality impairing the protein trafficking and adherens junctions by nephrotoxic drugs, autoimmune disease, FRST4, and an inherited disease (Lowe’s syndrome, and Dent’s disease). The last reason is the defective solute transports, especially the dysfunction of transporters resulting from FRST2 (NaPi), Fanconi-Bickel syndrome (GLUT2), lysinuric protein intolerance (cationic amino acid transporter), and Dent’s disease type I (amino acid transported by megalin and cubulin). These mechanisms facilitate the increase in oxidative stress, inflammation, and fibrosis, ultimately leading to apical dedifferentiation and defective solute resorption. As a consequence, patients with FS may exhibit hyperaminoaciduria, proteinuria, hyperphosphaturia, glycosuria, bicarbonaturia, and pyuria. FS, Fanconi syndrome; mtDNA, mitochondrial DNA; FRTS, Fanconi reno tubular syndrome; ROS, reactive oxygen species; MGRS, monoclonal gammopathies of renal significance.

Fig. 3.

ALDH2 exerts protective roles in various organs and cells by inhibiting ROS and 4-HNE. The main regulatory mechanism of ALDH2 in AKI. a: ALDH2 promotes mitochondrial biogenesis by interacting with PGC-1α. b: ALDH2 suppresses cell apoptosis by activating AKT/mTOR and NF-κb/IL-17 pathway. c: ALDH2 regulates autophagy by upregulating the Beclin/Bcl-2 pathway. ROS, reactive oxygen species; 4-HNE, 4-hydroxynonenal; PGC-1α, peroxisomal proliferator-γ coactivator-1α.