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Rare autosomal dominant tubulointerstitial kidney disease is caused by mutations in the genes encoding uromodulin (UMOD), hepatocyte nuclear factor-1β (HNF1B), renin (REN), and mucin-1 (MUC1). Multiple names have been proposed for these disorders, including ‘Medullary Cystic Kidney Disease (MCKD) type 2’, ‘Familial Juvenile Hyperuricemic Nephropathy (FJHN)’, or ‘Uromodulin-Associated Kidney Disease (UAKD)’ for UMOD-related diseases and ‘MCKD type 1’ for the disease caused by MUC1 mutations. The multiplicity of these terms, and the fact that cysts are not pathognomonic, creates confusion. Kidney Disease: Improving Global Outcomes (KDIGO) proposes adoption of a new terminology for this group of diseases using the term ‘Autosomal Dominant Tubulointerstitial Kidney Disease’ (ADTKD) appended by a gene-based subclassification, and suggests diagnostic criteria. Implementation of these recommendations is anticipated to facilitate recognition and characterization of these monogenic diseases. A better understanding of these rare disorders may be relevant for the tubulointerstitial fibrosis component in many forms of chronic kidney disease.

Uromodulin (Tamm–Horsfall protein) is the most abundant protein excreted in the urine under physiological conditions. It is exclusively produced in the kidney and secreted into the urine via proteolytic cleavage. Its biological function is still not fully understood. Uromodulin has been linked to water/electrolyte balance and to kidney innate immunity. Also, studies in knockout mice demonstrated that it has a protective role against urinary tract infections and renal stone formation. Mutations in the gene encoding uromodulin lead to rare autosomal dominant diseases, collectively referred to as uromodulin-associated kidney diseases. They are characterized by progressive tubulointerstitial damage, impaired urinary concentrating ability, hyperuricemia, renal cysts, and progressive renal failure. Novel in vivo studies point at intracellular accumulation of mutant uromodulin as a key primary event in the disease pathogenesis. Recently, genome-wide association studies identified uromodulin as a risk factor for chronic kidney disease (CKD) and hypertension, and suggested that the level of uromodulin in the urine could represent a useful biomarker for the development of CKD. In this review, we summarize these recent investigations, ranging from invalidation studies in mouse to Mendelian disorders and genome-wide associations, which led to a rediscovery of uromodulin and boosted the scientific and clinical interest for this long discovered molecule.

Key Points Uromodulin — the most abundant urinary protein — is exclusively produced by renal epithelial cells; in the tubular lumen uromodulin forms high-molecular weight filaments that constitute the matrix of hyaline casts Important functions of uromodulin include regulation of ion transport in the thick ascending limb, immunomodulation and protection against urinary tract infections and kidney stones Levels of uromodulin in the urine and in the blood, where it is present in lower amounts, are valuable biomarkers for tubular mass and renal function Rare mutations in UMOD cause autosomal dominant tubulointerstitial kidney disease; these mutations lead to retention of mutant uromodulin in the endoplasmic reticulum of tubular cells, tubulointerstitial damage and decreased levels of urinary uromodulin Common variants in the UMOD promoter are associated with risk of chronic kidney disease (CKD) and hypertension; the unusually high prevalence of UMOD risk alleles suggests pathogen-driven selective pressure UMOD represents a paradigm as a continuum of genetic disease risk, from rare mutations in Mendelian disease to common variants associated with complex traits including CKD and hypertension Uromodulin is the most abundant urinary protein. Here, the authors discuss the physiological roles of uromodulin, the mechanisms by which mutations in the UMOD gene, which encodes uromodulin, cause autosomal dominant tubulointerstitial kidney disease and the association of common UMOD variants with complex disorders in the general population. Uromodulin (also known as Tamm-Horsfall protein) is exclusively produced in the kidney and is the most abundant protein in normal urine. The function of uromodulin remains elusive, but the available data suggest that this protein might regulate salt transport, protect against urinary tract infection and kidney stones, and have roles in kidney injury and innate immunity. Interest in uromodulin was boosted by genetic studies that reported involvement of the UMOD gene, which encodes uromodulin, in a spectrum of rare and common kidney diseases. Rare mutations in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD), which leads to chronic kidney disease (CKD). Moreover, genome-wide association studies have identified common variants in UMOD that are strongly associated with risk of CKD and also with hypertension and kidney stones in the general population. These findings have opened up a new field of kidney research. In this Review we summarize biochemical, physiological, genetic and pathological insights into the roles of uromodulin; the mechanisms by which UMOD mutations cause ADTKD, and the association of common UMOD variants with complex disorders.

The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare large-effect variants in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD), while common low-impact variants strongly associate with kidney function and the risk of chronic kidney disease (CKD) in the general population. It is unknown whether intermediate-effect variants in UMOD contribute to CKD. Here, candidate intermediate-effect UMOD variants were identified using large-population and ADTKD cohorts. Biological and phenotypical effects were investigated using cell models, in silico simulations, patient samples, and international databases and biobanks. Eight UMOD missense variants reported in ADTKD are present in the Genome Aggregation Database (gnomAD), with minor allele frequency (MAF) ranging from 10−5 to 10−3. Among them, the missense variant p.Thr62Pro is detected in ∼1/1,000 individuals of European ancestry, shows incomplete penetrance but a high genetic load in familial clusters of CKD, and is associated with kidney failure in the 100,000 Genomes Project (odds ratio [OR] = 3.99 [1.84 to 8.98]) and the UK Biobank (OR = 4.12 [1.32 to 12.85). Compared with canonical ADTKD mutations, the p.Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD and an intermediate reduction of urinary uromodulin levels, in line with an intermediate trafficking defect in vitro and modest induction of endoplasmic reticulum (ER) stress. Identification of an intermediate-effect UMOD variant completes the spectrum of UMOD-associated kidney diseases and provides insights into the mechanisms of ADTKD and the genetic architecture of CKD.

Uromodulin (also known as Tamm–Horsfall protein) is a kidney-specific glycoprotein secreted bidirectionally into urine and into the circulation, and it is the most abundant protein in normal urine. Although the discovery of uromodulin predates modern medicine, its significance in health and disease has been rather enigmatic. Research studies have gradually revealed that uromodulin exists in multiple forms and has important roles in urinary and systemic homeostasis. Most uromodulin in urine is polymerized into highly organized filaments, whereas non-polymeric uromodulin is detected both in urine and in the circulation, and can have distinct roles. The interactions of uromodulin with the immune system, which were initially reported to be a key role of this protein, are now better understood. Moreover, the discovery that uromodulin is associated with a spectrum of kidney diseases, including acute kidney injury, chronic kidney disease and autosomal-dominant tubulointerstitial kidney disease, has further accelerated investigations into the role of this protein. These discoveries have prompted new questions and ushered in a new era in uromodulin research. Here, we delineate the latest discoveries in uromodulin biology and its emerging roles in modulating kidney and systemic diseases, and consider future directions, including its potential clinical applications.In this Review, the authors examine advances in uromodulin biology, including the existence of non-polymeric forms of the protein, its versatile functions, crosstalk with the immune system, its potential as a biomarker and its role in kidney disease, as well as considering how uromodulin might be targeted therapeutically.

The trafficking dynamics of uromodulin (UMOD), the most abundant protein in human urine, play a critical role in the pathogenesis of kidney disease. Monoallelic mutations in the UMOD gene cause autosomal dominant tubulointerstitial kidney disease (ADTKD- UMOD ), an incurable genetic disorder that leads to kidney failure. The disease is caused by the intracellular entrapment of mutant UMOD in kidney epithelial cells, but the precise mechanisms mediating disrupted UMOD trafficking remain elusive. Here, we report that transmembrane Emp24 protein transport domain–containing (TMED) cargo receptors TMED2, TMED9, and TMED10 bind UMOD and regulate its trafficking along the secretory pathway. Pharmacological targeting of TMEDs in cells, in human kidney organoids derived from patients with ADTKD- UMOD , and in mutant- UMOD -knockin mice reduced intracellular accumulation of mutant UMOD and restored trafficking and localization of UMOD to the apical plasma membrane. In vivo, the TMED-targeted small molecule also mitigated ER stress and markers of kidney damage and fibrosis. Our work reveals TMED-targeting small molecules as a promising therapeutic strategy for kidney proteinopathies.

Uromodulin is the most abundant protein in human urine, playing diverse roles, from providing frontline defense against uropathogens to regulating electrolyte balance via modulation of ion channels and cotransporters. In this issue of the JCI , Nanamatsu et al. unveil an alternatively spliced isoform of uromodulin that was dynamically induced in response to oxidative stress and tubular injury. Unlike the canonical secreted form, this isoform was retained in the cell, where it interacted with solute carrier proteins primarily localized to the mitochondrial membrane. Through these interactions, it modulated mitochondrial energetics and enhanced tubular cell resilience to injury. These findings broaden our understanding of uromodulin’s multifaceted functions, uncover an adaptive mechanism by which the kidney responds to cellular stress, and open avenues for therapeutic strategies targeting kidney injury and repair.

Background Autosomal dominant tubulointerstitial kidney disease caused by uromodulin mutation (ADTKD-UMOD) is a hereditary condition characterized by progressive renal dysfunction, often requiring renal replacement therapy by middle age. A notable feature is a strong family history of chronic kidney disease (CKD) and hyperuricemia; however, the absence of urinary abnormalities often delays diagnosis. To facilitate early CKD management, a diagnostic method that is simpler than genetic analysis yet strongly indicative of ADTKD-UMOD is needed. Methods Serum and urinary UMOD levels were measured in patients with ADTKD-UMOD, healthy controls, and patients with other diseases. We investigated whether reduced UMOD levels are a distinctive feature of ADTKD-UMOD. Results In 13 cases of ADTKD-UMOD, the serum UMOD (sUMOD) was 24.5 ± 13.9 ng/ml, the serum UMOD/GFR (sUMOD/GFR) was 1.23 ± 0.96, and the urinary UMOD/Cr (uUMOD/Cr) was 1.8 ± 0.9 mg/gcr. In the ADTKD-UMOD dataset, the sUMOD values were significantly lower than those in the other disease datasets. The UMOD/Cr and sUMOD/eGFR values also tended to be lower, although statistically significant differences were observed only in limited comparisons. The ROC analysis revealed that a serum UMOD concentration of < 56.4 ng/ml or sUMOD/GFR of < 1.71 is strongly suggestive of ADTKD-UMOD. Conclusions Measurement of UMOD protein levels is a useful tool for the diagnosis of　ADTKD-UMOD. Considering the stability of the procedure, serum UMOD may be more reliable than urinary UMOD measurement.

Tubular atrophy and interstitial fibrosis are basic renal pathological changes in autosomal dominant tubulointerstitial kidney disease (ADTKD). Reduced secretion or abnormal structure of uromodulin (UMOD) are recognised pathogenic factors of ADTKD. Studies show uromodulin binds complement factor H (cFH), enhancing its ability to inhibit complement activation. Overactivation of the complement system contributes to tubulointerstitial injury. Therefore, exploring the UMOD–tubulointerstitial fibrosis link may aid in the development of treatment for ADTKD‐UMOD. Immunofluorescence staining detected complement deposition in patients' kidneys. Uromodulin's binding affinity for cFH was assessed using microthermophoresis. The effect of this binding on cFH function was analysed using C3b degradation and erythrocyte hemolysis tests. Recombinant wild‐type and mutant uromodulin proteins were expressed and tested using the aforementioned methods. Complement factor B was detected in the kidneys of patients with ADTKD‐UMOD. Patient‐derived uromodulin showed reduced binding to cFH and decreased capacity to assist in C3b cleavage and hemolysis inhibition. Recombinant wild‐type uromodulin significantly enhanced C3b cleavage ( p < 0.001) and inhibited hemolysis ( p < 0.01). Uromodulin mutants showed reduced binding to cFH and limited ability to promote C3b degradation, with no significant hemolysis inhibition. Impaired interactions between mutants and cFH may lead to insufficient inhibition of complement activity, triggering tubulointerstitial fibrosis.

In the kidney, cells of thick ascending limb of the loop of Henle (TAL) are resistant to ischemic injury, despite high energy demands. This adaptive metabolic response is not fully understood even though the integrity of TAL cells is essential for recovery from acute kidney injury (AKI). TAL cells uniquely express uromodulin, the most abundant protein secreted in healthy urine. Here, we demonstrate that alternative splicing generates a conserved intracellular isoform of uromodulin, which contributes to metabolic adaptation of TAL cells. This splice variant was induced by oxidative stress and was upregulated by AKI that is associated with recovery, but not by severe AKI and chronic kidney disease (CKD). This intracellular variant was targeted to the mitochondria, increased NAD + and ATP levels, and protected TAL cells from hypoxic injury. Augmentation of this variant using antisense oligonucleotides after severe AKI improved the course of injury. These findings underscore an important role of condition-specific alternative splicing in adaptive energy metabolism to hypoxic stress. Enhancing this protective splice variant in TAL cells could become a therapeutic intervention for AKI.