RARE DISEASE
MUC1-related autosomal dominant tubulointerstitial kidney disease
MUC1-related autosomal dominant tubulointerstitial kidney disease
MUC1-related autosomal dominant tubulointerstitial kidney disease
Synonyms: ADTKD-MUC1, MCKD1, MUC1-related medullary cystic kidney disease, MUCI-related ADTKD, Medullary cystic kidney disease type 1
Synonyms: ADTKD-MUC1, MCKD1, MUC1-related medullary cystic kidney disease, MUCI-related ADTKD, Medullary cystic kidney disease type 1
Synonyms: ADTKD-MUC1, MCKD1, MUC1-related medullary cystic kidney disease, MUCI-related ADTKD, Medullary cystic kidney disease type 1
Drug discovery
0
drugs
With orphan designations
Overview
MUC1-related autosomal dominant tubulointerstitial kidney disease (ADTKD-MUC1) is a rare genetic disorder caused by frameshift mutations in the MUC1 gene, leading to progressive chronic kidney disease (CKD) via toxic accumulation of misfolded MUC1-fs protein in renal tubules. Patients exhibit bland urinalysis (minimal proteinuria/hematuria), slowly declining glomerular filtration rate (average annual loss: 1-3 mL/min/1.73m²), and autosomal dominant inheritance. Diagnosis relies on genetic testing, as biopsies show nonspecific interstitial fibrosis. End-stage kidney disease (ESKD) typically develops at a mean age of 45, though onset varies widely (20–70+ years). Kidney transplantation is curative, with no disease recurrence [1][2][8].
Therapies
Standard CKD management (BP control, anemia/gout treatment) [2][8]
Kidney transplantation (definitive treatment; 100% survival comparable to general ESKD population) [1][8]
Emerging therapies include BRD4780, a small molecule that degrades MUC1-fs by rerouting it to lysosomes, showing efficacy in preclinical models [5][14]. Clinical trials are anticipated to evaluate its safety and broader applicability to proteinopathies [5][14][11].
Categories: rare genetic diseases, rare renal diseases, rare transplant-related disorders
Research Papers
22 drug discovery papers about MUC1-related autosomal dominant tubulointerstitial kidney disease, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
22 drug discovery papers about MUC1-related autosomal dominant tubulointerstitial kidney disease, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-04-29 | Uromodulin p.His36Tyr promotes macrophage pyroptosis via App-Cd74 signaling to drive renal inflammation in ADTKD.
Autosomal dominant tubulointerstitial kidney disease -UMOD is characterized by progressive renal interstitial inflammation and fibrosis. However, its underlying mechanisms remain unclear. Here, we identify a large ADTKD pedigree harboring a novel UMOD p.H36Y mutation. Using CRISPR/Cas9 technology, we generated a UmodH36Y/+ mouse model that recapitulates the key phenotypes observed in affected individuals, including renal dysfunction, cyst formation, and interstitial inflammation. Multi-omics analyses in kidneys from male UmodH36Y/+ mice revealed marked macrophage pyroptosis. Mechanistically, the Umod p.H36Y variant activated the amyloid precursor protein (App)-Cd74 axis which mediated the crosstalk between renal mutant tubular cells and macrophages. This axis sustains NF-κB pathway activation in macrophages, initiating pyroptosis and pro-inflammatory cytokine release. The same mechanism is recapitulated in the UMOD p.Trp31Cys cell model. Notably, Pharmacologic inhibition using ARN2966, a small-molecule App inhibitor, attenuated renal injury in male UmodH36Y/+ mice. Collectively, these findings uncover a targetable pathway in ADTKD-UMOD.
2026-02-03 | Calorie Restriction Leads to Degradation of Mutant Uromodulin and Ameliorates Inflammation and Fibrosis in UMOD -Related Kidney Disease.
Calorie restriction stimulated autophagy and degradation of mutant uromodulin, leading to amelioration of cell stress and tubular damage. At early disease stage, calorie restriction largely reverted autosomal dominant tubulointerstitial kidney disease (ADTKD)- UMOD phenotype, preventing inflammation, fibrosis, and kidney function decline. At advanced disease stage, calorie restriction significantly delayed disease progression and worsening of kidney function. Mutations in UMOD , encoding uromodulin, lead to autosomal dominant tubulointerstitial kidney disease (ADTKD), a genetic cause of kidney failure. UMOD mutations have a common gain-of-toxic-function effect, causing mutant uromodulin retention in the endoplasmic reticulum (ER). This leads to ER stress, alteration of protein homeostasis and mitochondrial dynamics, defective autophagy, and increased cell death. Calorie restriction exerts a beneficial role in diseases characterized by accumulation of pathogenic protein and inflammation, by modulating several pathways, including autophagy induction and suppression of inflammation and fibrosis. Given the relevance of these features in ADTKD, we investigated the effect of calorie restriction on disease onset and progression. Transgenic mice expressing C147W uromodulin (Tg Umod C147W ) were subjected to a moderate (30%) calorie restriction regimen for 15 or 24 weeks, starting at different stages of disease progression. Calorie restriction restored autophagy, as shown by decreased P62 punctae and quenched mammalian target of rapamycin (mTOR) activation specifically in mutant uromodulin-expressing cells, and it recovered expression of key ER-phagy receptor genes, with a concomitant, striking reduction of mutant uromodulin ER retention. In presymptomatic Tg Umod C147W mice, calorie restriction alleviated epithelial cell stress. This, likely along with a direct anti-inflammatory effect of calorie restriction, prevented inflammation and progressive decline of kidney function. At this early disease stage, calorie restriction ameliorated the already established kidney damage and reduced fibrosis, suggesting reversal of ADTKD phenotype. Calorie restriction was also effective in significantly delaying disease progression in Tg Umod C147W mice with advanced disease and already compromised kidney function. Calorie restriction enhanced autophagy and uromodulin degradation, counteracting the primary effect of UMOD mutations, and significantly ameliorated kidney disease onset and progression.
2026-02-03 | Autosomal dominant tubulointerstitial kidney disease – from a diagnostic desert to a more nuanced landscape of roses and thorns
Abstract Autosomal dominant tubulointerstitial kidney disease (ADTKD) constitutes a spectrum of rare, but underdiagnosed renal disorders. ADTKD presents with a bland urinary sediment (no hematuria and little to no proteinuria), usually has no extrarenal manifestations (with the exception of HNF1B- associated disease), and results in a slowly progressive chronic kidney disease. Renal failure typically occurs in the fourth to fifth decade of life. Despite a uniform clinical picture, there is substantial interfamilial- and intrafamilial diversity in progression of CKD sometimes ranging from before the third to beyond the sixth decade of life. ADTKD shows modest genetic heterogeneity, with four main types ( UMOD , MUC1 , HNF1B , and REN ) accounting for the vast majority of cases. However, sometimes ADTKD is used as an umbrella term for a broader number of isolated or syndromal conditions that may present with an ADTKD phenotype. The two most common ADTKD types caused by pathogenic variants in the glycoproteins uromodulin ( UMOD ), mucin 1 ( MUC1 ), and the enzyme renin ( REN ) show striking similarities in their molecular pathophysiology and are considered toxic proteinopathies. From a spectrum of kidney disease virtually unknown to the public and to large parts of the medical community before the identification of UMOD as the first identified cause of ADTKD (then termed MCKD2) in 2002, ADTKD is increasingly recognized as a leading genetic cause of kidney disease in adults. The identification of MUC1 as the cause for the second main type has greatly stimulated research on all aspects of ADTKD and unveiled important molecular insights into its underlying pathophsiology. Our molecular knowledge on common ADTKD forms has passed the critical threshold required for developing targeted therapeutic strategies and personalized treatment approaches can be expected in the near future.
2025-10-03 | An Observational Study of SGLT2 Inhibitors and Their Use in Autosomal Dominant Tubulointerstitial Kidney Disease.
There are no specific treatments available for autosomal dominant tubulointerstitial kidney disease (ADTKD). As SGLT2 inhibitors have proven effective in other forms of CKD, we performed an observational study to determine their safety and effect on kidney function in ADTKD. We obtained clinical and laboratory data before and after starting an SGLT2 inhibitor on 27 individuals with ADTKD. We created a propensity-matched cohort from a Wake Forest prospective ADTKD observational study. Of the 27 individuals, 12 stopped medication prior to one year due to concerns about the (anticipated) acute rise in serum creatinine. There were no adverse effects. The slope of eGFR after SGLT 2 inhibitor initiation was - 2.61 ± 2.58 ml/min/1.73m2, which was not significantly different from the eGFR slope prior to initiation of SGLT2 inhibitors (-3.13 ± 5.39 ml/min/1.73 m2 (p = 0.71)) or from 30 propensity-matched controls (-2.25 ± 2.39 ml/min/1.73 m2 (p = 0.83)). Hemoglobin and plasma and urine KIM-1 levels did not change after starting SGLT2 inhibitors. SGLT2 inhibitors were well tolerated in ADTKD patients. There was neither a rise in hemoglobin levels nor a fall in plasma or urinary KIM-1 levels, suggesting that these agents may not be beneficial in ADTKD.
2025-03-01 | Biomarkers in Autosomal Dominant Tubulointerstitial Kidney Disease
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is increasingly recognized as a significant contributor to chronic kidney disease (CKD), attributed to mutations in at least five genes: UMOD, MUC1, HNF1B, REN, and SEC61A1 . ADTKD typically presents as slowly progressive CKD with variable clinical features such as hyperuricemia and tubular proteinuria, complicating its diagnosis. The disease is often undiagnosed until advanced stages due to its insidious onset and nonspecific clinical indicators. This review synthesizes current knowledge on the clinical manifestations, pathological features, and emerging biomarkers of ADTKD, emphasizing the complexity and heterogeneity of the disease. Treatment options are limited, most current approaches focus on controlling blood pressure, uric acid levels, and anemia to delay kidney failure, with uncertain efficacy in slowing disease progression. Integrative strategies, including traditional Chinese medicine (TCM), have shown promise in mitigating core pathological processes such as renal interstitial fibrosis and may offer a complementary avenue to improve patient outcomes. Effective biomarkers remain crucial for early diagnosis and personalized interventions, and future integration of genomics, proteomics, and metabolomics is warranted to reveal the biological networks and molecular mechanisms of ADTKD, identifying new biomarkers and potential therapeutic targets.
antibodies
2026-03-25 | WCN26-4708 A CASE OF ADTKD-MUC1 DIAGNOSED BY LONG-READ SEQUENCING OF THE MUC1 VNTR REGION
Autosomal Dominant Tubulointerstitial Kidney Disease caused by MUC1 (ADTKD-MUC1) is a progressive inherited kidney disease often characterized by slow decline in kidney function and subtle or absent urinary findings. Its definitive diagnosis requires genetic analysis, which is frequently complicated by the unique, repetitive genomic structure of the MUC1 gene.
2026-01-02 | Case Report: UMOD gene mutation and phenotypic overlap with REN in autosomal dominant tubulointerstitial kidney disease.
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare monogenic kidney disorder characterized by progressive tubular atrophy and interstitial fibrosis. It is primarily associated with pathogenic variants in genes such as UMOD (uromodulin), REN (renin), MUC1 (mucin 1), and HNF1B (hepatocyte nuclear factor 1-beta). We report a unique Chinese case of ADTKD-UMOD in a patient carrying a UMOD gene mutation. The clinical presentation was complex: in addition to the classic features of UMOD mutations (hyperuricemia and gout), the patient exhibited endocrine and metabolic abnormalities typically linked to REN gene defects (ADTKD-REN), including anemia, hypotension, and hyporeninemic hypoaldosteronism. However, renal biopsy and genetic testing ultimately confirmed the diagnosis as ADTKD caused by a heterozygous missense mutation in UMOD gene.
2025-10-27 | Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) in Chinese Patients.
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is recognized as a significant cause of genetic kidney disease. However, data from Asian populations remains limited. We evaluated 70 patients meeting KDIGO clinical criteria for ADTKD at Peking University First Hospital between 2010 and 2024. Genetic testing was performed using whole exome sequencing (WES), with PacBio long-read sequencing employed for cases meeting clinical criteria but lacking identifiable causal variants. Plasma and urinary uromodulin levels were measured and compared between ADTKD, IgA nephropathy, and polycystic kidney disease patients. In this Chinese cohort of 70 ADTKD patients, ADTKD-UMOD was the most prevalent subtype, accounting for 51% of cases, followed by ADTKD-HNF1B (23%), ADTKD-MUC1 (20%), and ADTKD-REN (6%). A notable 69% of patients had a family history of chronic kidney disease, with de novo variants present in 50% of ADTKD-HNF1B cases. The mean age at diagnosis was 32 ± 11 years, and patients exhibited an average estimated glomerular filtration rate (eGFR) of 46 ± 21 mL/min/1.73m². Importantly, uromodulin levels proved to be a highly effective biomarker, distinguishing ADTKD-UMOD from other subtypes and kidney diseases with impressive diagnostic accuracy, achieving area under the curve (AUC) values of 0.85 for plasma, 0.86 for urine, and 0.93 when combined. This study establishes the first ADTKD cohort in China, revealing distinctive genetic and clinical features, including a high prevalence of UMOD and HNF1B variants. Urine and plasma uromodulin proved to be reliable biomarkers for diagnosing and monitoring ADTKD-UMOD. Incorporating uromodulin testing into clinical practice may improve early diagnosis and management of ADTKD and related kidney diseases.
2025-08-21 | Autosomal Dominant Tubulointerstitial Kidney Disease: A Review.
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an increasingly recognized rare condition with 3 primary characteristics: autosomal dominant inheritance, bland urinary sediment (absence of hematuria and proteinuria), and chronic kidney disease (CKD) leading to kidney failure (need for kidney replacement therapy or kidney transplantation) between 20 and 80 years of age, with a mean age of kidney failure of approximately 45 years. Pathogenic variants in UMOD, MUC1, REN, and APOA4 have been identified as causative in ADTKD families. Prior to 2000, ADTKD was only diagnosed clinically and had been described in fewer than 50 families. However, with the advent of genetic testing and a better understanding of this condition, ADTKD is being increasingly recognized and is the third most common monogenic cause of kidney failure. The purpose of this review is to provide an understanding of the clinical characteristics of ADTKD and its subtypes with a practical approach to diagnosis and management for clinical nephrologists.
2025-07-25 | Quantifying clinical and genetic factors influencing rate and severity of autosomal dominant tubulointerstitial kidney disease progression.
Autosomal dominant tubulointerstitial kidney disease (ADTKD), caused by mutations in UMOD and MUC1 genes, leads to tubular damage and fibrosis, ultimately resulting in kidney failure (KF). This study investigated clinical and genetic factors influencing the rate and severity of ADTKD progression by developing quantitative models. An estimated glomerular filtration rate (eGFR) of 10 mL/min/1.73 m2 was used to define KF, corresponding to dialysis initiation. Natural history data from the Wake Forest University School of Medicine study were used to develop the models for UMOD (n = 371) and MUC1 (n = 233) disease types (age ≥ 18 years). Longitudinal change in eGFR and time-to-KF were quantified using nonlinear mixed-effects and parametric time-to-event modeling approaches, respectively, in Monolix (version 2024R1). Sigmoid Imax functions with steepness parameters varying before and after inflection points best captured eGFR decline. Patients with UMOD and MUC1 disease variants exhibited a similar initial shallow steepness ( ≈ 1), but after inflection, each declined rapidly. MUC1 patients progressed faster than UMOD during the post-inflection phase (γ₂ = 10.23 vs. 6.34). eGFR at first clinic visit (eGFR_FCV) and age at first clinic visit (AFCV) significantly affected between-subject variability in eGFR decline. A Weibull hazard function best described the time to KF. In UMOD, males reached Te (the age at which approximately 36.8% of individuals remain free from KF) 4 years earlier than females on average (β_Te_Male = -0.07), indicating faster progression in males. Older AFCV was associated with slower progression to KF (β_Te_AFCV = 0.59 for UMOD and 0.81 for MUC1). These models may help enable quantitative data-driven subgroup analysis in the future, optimizing inclusion/exclusion criteria for ADTKD clinical trials.
small molecules
2026-04-29 | Uromodulin p.His36Tyr promotes macrophage pyroptosis via App-Cd74 signaling to drive renal inflammation in ADTKD.
Autosomal dominant tubulointerstitial kidney disease -UMOD is characterized by progressive renal interstitial inflammation and fibrosis. However, its underlying mechanisms remain unclear. Here, we identify a large ADTKD pedigree harboring a novel UMOD p.H36Y mutation. Using CRISPR/Cas9 technology, we generated a UmodH36Y/+ mouse model that recapitulates the key phenotypes observed in affected individuals, including renal dysfunction, cyst formation, and interstitial inflammation. Multi-omics analyses in kidneys from male UmodH36Y/+ mice revealed marked macrophage pyroptosis. Mechanistically, the Umod p.H36Y variant activated the amyloid precursor protein (App)-Cd74 axis which mediated the crosstalk between renal mutant tubular cells and macrophages. This axis sustains NF-κB pathway activation in macrophages, initiating pyroptosis and pro-inflammatory cytokine release. The same mechanism is recapitulated in the UMOD p.Trp31Cys cell model. Notably, Pharmacologic inhibition using ARN2966, a small-molecule App inhibitor, attenuated renal injury in male UmodH36Y/+ mice. Collectively, these findings uncover a targetable pathway in ADTKD-UMOD.
2026-02-03 | Calorie Restriction Leads to Degradation of Mutant Uromodulin and Ameliorates Inflammation and Fibrosis in UMOD -Related Kidney Disease.
Calorie restriction stimulated autophagy and degradation of mutant uromodulin, leading to amelioration of cell stress and tubular damage. At early disease stage, calorie restriction largely reverted autosomal dominant tubulointerstitial kidney disease (ADTKD)- UMOD phenotype, preventing inflammation, fibrosis, and kidney function decline. At advanced disease stage, calorie restriction significantly delayed disease progression and worsening of kidney function. Mutations in UMOD , encoding uromodulin, lead to autosomal dominant tubulointerstitial kidney disease (ADTKD), a genetic cause of kidney failure. UMOD mutations have a common gain-of-toxic-function effect, causing mutant uromodulin retention in the endoplasmic reticulum (ER). This leads to ER stress, alteration of protein homeostasis and mitochondrial dynamics, defective autophagy, and increased cell death. Calorie restriction exerts a beneficial role in diseases characterized by accumulation of pathogenic protein and inflammation, by modulating several pathways, including autophagy induction and suppression of inflammation and fibrosis. Given the relevance of these features in ADTKD, we investigated the effect of calorie restriction on disease onset and progression. Transgenic mice expressing C147W uromodulin (Tg Umod C147W ) were subjected to a moderate (30%) calorie restriction regimen for 15 or 24 weeks, starting at different stages of disease progression. Calorie restriction restored autophagy, as shown by decreased P62 punctae and quenched mammalian target of rapamycin (mTOR) activation specifically in mutant uromodulin-expressing cells, and it recovered expression of key ER-phagy receptor genes, with a concomitant, striking reduction of mutant uromodulin ER retention. In presymptomatic Tg Umod C147W mice, calorie restriction alleviated epithelial cell stress. This, likely along with a direct anti-inflammatory effect of calorie restriction, prevented inflammation and progressive decline of kidney function. At this early disease stage, calorie restriction ameliorated the already established kidney damage and reduced fibrosis, suggesting reversal of ADTKD phenotype. Calorie restriction was also effective in significantly delaying disease progression in Tg Umod C147W mice with advanced disease and already compromised kidney function. Calorie restriction enhanced autophagy and uromodulin degradation, counteracting the primary effect of UMOD mutations, and significantly ameliorated kidney disease onset and progression.
2026-02-03 | Autosomal dominant tubulointerstitial kidney disease – from a diagnostic desert to a more nuanced landscape of roses and thorns
Abstract Autosomal dominant tubulointerstitial kidney disease (ADTKD) constitutes a spectrum of rare, but underdiagnosed renal disorders. ADTKD presents with a bland urinary sediment (no hematuria and little to no proteinuria), usually has no extrarenal manifestations (with the exception of HNF1B- associated disease), and results in a slowly progressive chronic kidney disease. Renal failure typically occurs in the fourth to fifth decade of life. Despite a uniform clinical picture, there is substantial interfamilial- and intrafamilial diversity in progression of CKD sometimes ranging from before the third to beyond the sixth decade of life. ADTKD shows modest genetic heterogeneity, with four main types ( UMOD , MUC1 , HNF1B , and REN ) accounting for the vast majority of cases. However, sometimes ADTKD is used as an umbrella term for a broader number of isolated or syndromal conditions that may present with an ADTKD phenotype. The two most common ADTKD types caused by pathogenic variants in the glycoproteins uromodulin ( UMOD ), mucin 1 ( MUC1 ), and the enzyme renin ( REN ) show striking similarities in their molecular pathophysiology and are considered toxic proteinopathies. From a spectrum of kidney disease virtually unknown to the public and to large parts of the medical community before the identification of UMOD as the first identified cause of ADTKD (then termed MCKD2) in 2002, ADTKD is increasingly recognized as a leading genetic cause of kidney disease in adults. The identification of MUC1 as the cause for the second main type has greatly stimulated research on all aspects of ADTKD and unveiled important molecular insights into its underlying pathophsiology. Our molecular knowledge on common ADTKD forms has passed the critical threshold required for developing targeted therapeutic strategies and personalized treatment approaches can be expected in the near future.
2025-10-03 | An Observational Study of SGLT2 Inhibitors and Their Use in Autosomal Dominant Tubulointerstitial Kidney Disease.
There are no specific treatments available for autosomal dominant tubulointerstitial kidney disease (ADTKD). As SGLT2 inhibitors have proven effective in other forms of CKD, we performed an observational study to determine their safety and effect on kidney function in ADTKD. We obtained clinical and laboratory data before and after starting an SGLT2 inhibitor on 27 individuals with ADTKD. We created a propensity-matched cohort from a Wake Forest prospective ADTKD observational study. Of the 27 individuals, 12 stopped medication prior to one year due to concerns about the (anticipated) acute rise in serum creatinine. There were no adverse effects. The slope of eGFR after SGLT 2 inhibitor initiation was - 2.61 ± 2.58 ml/min/1.73m2, which was not significantly different from the eGFR slope prior to initiation of SGLT2 inhibitors (-3.13 ± 5.39 ml/min/1.73 m2 (p = 0.71)) or from 30 propensity-matched controls (-2.25 ± 2.39 ml/min/1.73 m2 (p = 0.83)). Hemoglobin and plasma and urine KIM-1 levels did not change after starting SGLT2 inhibitors. SGLT2 inhibitors were well tolerated in ADTKD patients. There was neither a rise in hemoglobin levels nor a fall in plasma or urinary KIM-1 levels, suggesting that these agents may not be beneficial in ADTKD.
2025-03-01 | Biomarkers in Autosomal Dominant Tubulointerstitial Kidney Disease
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is increasingly recognized as a significant contributor to chronic kidney disease (CKD), attributed to mutations in at least five genes: UMOD, MUC1, HNF1B, REN, and SEC61A1 . ADTKD typically presents as slowly progressive CKD with variable clinical features such as hyperuricemia and tubular proteinuria, complicating its diagnosis. The disease is often undiagnosed until advanced stages due to its insidious onset and nonspecific clinical indicators. This review synthesizes current knowledge on the clinical manifestations, pathological features, and emerging biomarkers of ADTKD, emphasizing the complexity and heterogeneity of the disease. Treatment options are limited, most current approaches focus on controlling blood pressure, uric acid levels, and anemia to delay kidney failure, with uncertain efficacy in slowing disease progression. Integrative strategies, including traditional Chinese medicine (TCM), have shown promise in mitigating core pathological processes such as renal interstitial fibrosis and may offer a complementary avenue to improve patient outcomes. Effective biomarkers remain crucial for early diagnosis and personalized interventions, and future integration of genomics, proteomics, and metabolomics is warranted to reveal the biological networks and molecular mechanisms of ADTKD, identifying new biomarkers and potential therapeutic targets.
antibodies
2026-03-25 | WCN26-4708 A CASE OF ADTKD-MUC1 DIAGNOSED BY LONG-READ SEQUENCING OF THE MUC1 VNTR REGION
Autosomal Dominant Tubulointerstitial Kidney Disease caused by MUC1 (ADTKD-MUC1) is a progressive inherited kidney disease often characterized by slow decline in kidney function and subtle or absent urinary findings. Its definitive diagnosis requires genetic analysis, which is frequently complicated by the unique, repetitive genomic structure of the MUC1 gene.
2026-01-02 | Case Report: UMOD gene mutation and phenotypic overlap with REN in autosomal dominant tubulointerstitial kidney disease.
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare monogenic kidney disorder characterized by progressive tubular atrophy and interstitial fibrosis. It is primarily associated with pathogenic variants in genes such as UMOD (uromodulin), REN (renin), MUC1 (mucin 1), and HNF1B (hepatocyte nuclear factor 1-beta). We report a unique Chinese case of ADTKD-UMOD in a patient carrying a UMOD gene mutation. The clinical presentation was complex: in addition to the classic features of UMOD mutations (hyperuricemia and gout), the patient exhibited endocrine and metabolic abnormalities typically linked to REN gene defects (ADTKD-REN), including anemia, hypotension, and hyporeninemic hypoaldosteronism. However, renal biopsy and genetic testing ultimately confirmed the diagnosis as ADTKD caused by a heterozygous missense mutation in UMOD gene.
2025-10-27 | Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) in Chinese Patients.
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is recognized as a significant cause of genetic kidney disease. However, data from Asian populations remains limited. We evaluated 70 patients meeting KDIGO clinical criteria for ADTKD at Peking University First Hospital between 2010 and 2024. Genetic testing was performed using whole exome sequencing (WES), with PacBio long-read sequencing employed for cases meeting clinical criteria but lacking identifiable causal variants. Plasma and urinary uromodulin levels were measured and compared between ADTKD, IgA nephropathy, and polycystic kidney disease patients. In this Chinese cohort of 70 ADTKD patients, ADTKD-UMOD was the most prevalent subtype, accounting for 51% of cases, followed by ADTKD-HNF1B (23%), ADTKD-MUC1 (20%), and ADTKD-REN (6%). A notable 69% of patients had a family history of chronic kidney disease, with de novo variants present in 50% of ADTKD-HNF1B cases. The mean age at diagnosis was 32 ± 11 years, and patients exhibited an average estimated glomerular filtration rate (eGFR) of 46 ± 21 mL/min/1.73m². Importantly, uromodulin levels proved to be a highly effective biomarker, distinguishing ADTKD-UMOD from other subtypes and kidney diseases with impressive diagnostic accuracy, achieving area under the curve (AUC) values of 0.85 for plasma, 0.86 for urine, and 0.93 when combined. This study establishes the first ADTKD cohort in China, revealing distinctive genetic and clinical features, including a high prevalence of UMOD and HNF1B variants. Urine and plasma uromodulin proved to be reliable biomarkers for diagnosing and monitoring ADTKD-UMOD. Incorporating uromodulin testing into clinical practice may improve early diagnosis and management of ADTKD and related kidney diseases.
2025-08-21 | Autosomal Dominant Tubulointerstitial Kidney Disease: A Review.
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an increasingly recognized rare condition with 3 primary characteristics: autosomal dominant inheritance, bland urinary sediment (absence of hematuria and proteinuria), and chronic kidney disease (CKD) leading to kidney failure (need for kidney replacement therapy or kidney transplantation) between 20 and 80 years of age, with a mean age of kidney failure of approximately 45 years. Pathogenic variants in UMOD, MUC1, REN, and APOA4 have been identified as causative in ADTKD families. Prior to 2000, ADTKD was only diagnosed clinically and had been described in fewer than 50 families. However, with the advent of genetic testing and a better understanding of this condition, ADTKD is being increasingly recognized and is the third most common monogenic cause of kidney failure. The purpose of this review is to provide an understanding of the clinical characteristics of ADTKD and its subtypes with a practical approach to diagnosis and management for clinical nephrologists.
2025-07-25 | Quantifying clinical and genetic factors influencing rate and severity of autosomal dominant tubulointerstitial kidney disease progression.
Autosomal dominant tubulointerstitial kidney disease (ADTKD), caused by mutations in UMOD and MUC1 genes, leads to tubular damage and fibrosis, ultimately resulting in kidney failure (KF). This study investigated clinical and genetic factors influencing the rate and severity of ADTKD progression by developing quantitative models. An estimated glomerular filtration rate (eGFR) of 10 mL/min/1.73 m2 was used to define KF, corresponding to dialysis initiation. Natural history data from the Wake Forest University School of Medicine study were used to develop the models for UMOD (n = 371) and MUC1 (n = 233) disease types (age ≥ 18 years). Longitudinal change in eGFR and time-to-KF were quantified using nonlinear mixed-effects and parametric time-to-event modeling approaches, respectively, in Monolix (version 2024R1). Sigmoid Imax functions with steepness parameters varying before and after inflection points best captured eGFR decline. Patients with UMOD and MUC1 disease variants exhibited a similar initial shallow steepness ( ≈ 1), but after inflection, each declined rapidly. MUC1 patients progressed faster than UMOD during the post-inflection phase (γ₂ = 10.23 vs. 6.34). eGFR at first clinic visit (eGFR_FCV) and age at first clinic visit (AFCV) significantly affected between-subject variability in eGFR decline. A Weibull hazard function best described the time to KF. In UMOD, males reached Te (the age at which approximately 36.8% of individuals remain free from KF) 4 years earlier than females on average (β_Te_Male = -0.07), indicating faster progression in males. Older AFCV was associated with slower progression to KF (β_Te_AFCV = 0.59 for UMOD and 0.81 for MUC1). These models may help enable quantitative data-driven subgroup analysis in the future, optimizing inclusion/exclusion criteria for ADTKD clinical trials.
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