Tubulointerstitial Kidney Disease Research Articles

#276 ADTKD genetic diagnostics in Europe: where do we stand and what is needed?

Abstract Background and Aims We are the first European patient organization to pursue the goal of raising awareness of the monogenic kidney disease ADTKD (autosomal dominant tubulointerstitial kidney disease) and supporting its research (www.adtkd.de/en-gb). To date, causative mutations are known in at least five disease genes (UMOD, MUC1, REN, HNF1B, SEC61A1) [1] and one can expect that even more disease genes exist. There are already strong international collaborations to define the clinical course of ADTKD [2] and to evaluate a targeted therapy in clinical trials [3]. Clinical registries form the basis for the inclusion of patients, preferably at an early stage of the disease. Such a registry already exists in the USA and is currently being established in Europe (ADTKD-Net) as part of the European Joint Program on Rare Diseases (EJP RD). Due to its non-specific and variable clinical characteristics, ADTKD is often misdiagnosed or not diagnosed at all. Experts therefore suspect a high number of unreported cases. There are also challenges in genetic diagnostics. While next generation sequencing (NGS) panels have been established for ADTKD, they are usually unable to detect pathogenic MUC1 variants due to their specific location in the genome. This is the insertion of an additional cytosine (dupC) in a VNTR (Variable Number of Tandem Repeats) domain of the MUC1 gene, which cannot be detected by NGS and therefore requires special procedures such as SnaPshot Minisequencing [4] or VNtyper [5]. For instance, there are only two laboratories that can perform this specific MUC1 testing in Germany to date. The aim of this study is to assess the status quo of ADTKD diagnostics in Europe. We hypothesize that there is a lack of appropriate structures to adequately and reliably diagnose ADTKD, notably ADTKD-MUC1. The study is intended to help identify deficits and obstacles in order to address these in a targeted manner. Methods We used Survey Monkey to create a digital survey, which we sent by email to around 50 European ADTKD experts. They were asked to answer 7 key questions (Fig. 1). For the selection of suitable ADTKD experts, we use various sources such as publications on ADTKD in PubMed, the Expert Finder and the European Patient Advocacy Groups (ePAG) in the European Reference Network for Rare Kidney Diseases (ERKNet) and our own network. Our aim is to cover at least the 30 largest countries in Europe in terms of population. Results Results will be presented at the ERA conference. Conclusion With our survey we would like to substantiate the hypothesis that the possibilities of molecular diagnostics of ADTKD in Europe are currently insufficient. Based on our results, short and long-term measures should be taken to remedy potential deficits so that as many patients as possible can be identified and have access to therapeutic options in the future. Another interesting aspect is the awareness of ADTKD among European nephrologists. This could be a future activity of our patient organization.

Outcomes of hemolytic-uremic syndrome in children

It is proved that HUS in children is the cause of the formation and progression of renal dysfunction with the formation of CKD. At the same time, the outcomes of HUS in childhood remain insufficiently studied. Purpose. To establish the outcomes of hemolytic-uremic syndrome in children and to develop an algorithm for their prediction.Results. Seasonality is established (May and June) HUS in children, an increase in the incidence rate. In the structure of HUS in children of the Orenburg region, STEC-HUS prevails (96.5 %), more often (68.6 %) in infants and young children. Chronic kidney diseases associated with HUS are characterized by a violation of the structure of the kidneys, a decrease in intrarenal hemodynamics, increased blood pressure, microalbuminuria, tubular dysfunction and a decrease in glomerular filtration rate in combination with an increase in the level of endothelin-1 blood, cystatin From urine and blood, uNGAL. An increase in endothelin-1 in blood, cystatin From urine and blood, uNGAL correlates with the level of increased blood pressure, a decrease in intrarenal hemodynamics, GFR and tubular dysfunction and are pathogenetic criteria for kidney damage in HUS convalescent children. Discussion. Clinical and pathogenetic markers of the formation of CKD have been established: an increase in the level of blood EТ-1, blood cystatin, urine lipocalin in combination with arterial hypertension, a decrease in GFR and intrarenal hemodynamics, an increase in tubular dysfunction and the level of microalbuminuria. Conclusion. The outcomes of HUS in children are- favorable (recovery); unfavorable (formation of chronic kidney pathology): TIBP, occurring with isolated urinary syndrome; nephropathies with isolated prenephrotic proteinuria; chronic kidney disease; fatal outcome. The developed «Algorithm for predicting chronic kidney damage in children with HUS convalescents», «Method for predicting tubulo-interstitial kidney disease in children associated with hemolytic-uremic syndrome», allow optimizing the early diagnosis of chronic kidney pathology in children after HUS, contribute to the timely appointment of preventive measures to prevent the progression of renal dysfunction and is recommended for use in the practice of pediatricians, nephrologists.

Case-inspired exploration of renin mutations in autosomal dominant tubulointerstitial kidney disease: not all paths lead to the endoplasmic reticulum.

Autosomal dominant tubulointerstitial kidney disease (ADTKD) results from mutations in various genes, including REN, UMOD, MUC1, and HNF1B. ADTKD due to REN mutations (ADTKD-REN) is often characterized as a proteinopathy that triggers the endoplasmic reticulum stress (ERS) cascade, potentially sharing similarities with ADTKD-UMOD and ADTKD-MUC1 at the cellular level. This study, inspired by a patient harboring a W17R mutation, investigates ERS activation by this mutation alongside two other renin variants, W10R and L381P. We established stable cell lines expressing both wild-type and mutated renin forms (W17R, W10R, and L381P). Using luciferase reporter assays, RT-qPCR, and confocal microscopy, we evaluated ERS activation, determined the cellular localization of the renin variants, and characterized the mitochondrial network in the W17R line. The L381P line exhibited ERS activation, including transcriptional upregulation of MANF and CRELD2. No ERS activation was observed in the W17R line, while the W10R line exhibited intermediate characteristics. Notably, the W17R variant was misrouted to the mitochondria resulting in changes of the mitochondrial network organisation. ERS activation is not a universal response to different renin mutations in ADTKD-REN. The pathogenesis of the W17R mutation may involve mitochondrial dysfunction rather than the ER pathway, albeit further research is needed to substantiate this hypothesis fully. Testing CRELD2 and MANF as targeted therapy markers for a specific subgroup of ADTKD-REN patients is recommended. Additionally, fludrocortisone treatment has shown efficacy in stabilizing the renal function of our patient over a four-year period without significant side effects.

Genetic Diagnosis of Adult Hemodialysis Patients With Unknown Etiology

Kidney disease of unknown etiology accounts for 1 in 10 adult end-stage renal disease (ESRD) cases worldwide. The aim of this study is to clarify the genetic background of patients with chronic kidney disease (CKD) of unknown etiology who initiated renal replacement therapy (RRT) in adulthood. This is a multicenter cross-sectional cohort study. Of the 1164 patients who attended 4 dialysis clinics in Japan, we first selected patients who started RRT between the ages of 20 and 49 years. After excluding patients with apparent causes of CKD (e.g., diabetic nephropathy, polycystic kidney disease (PKD) with family history, patients who underwent renal biopsy), 90 patients with CKD of unknown cause were included. The 298 genes associated with CKD were analyzed using capture-based targeted next-generation sequencing. Of the 90 patients, 10 (11.1%) had pathogenic variants in CKD-causing genes and 17 (18.9%) had variant of unknown significance (VUS). Three patients had PKD1 pathogenic variants, and 1 patient had PKD1 and COL4A4 pathogenic variants. In addition, 2 patients were diagnosed with atypical hemolytic uremic syndrome (aHUS) due to C3 or CFHR5. One patient each was diagnosed with Alport syndrome due to COL4A4 and COL4A3 variants, nephronophthisis due to NPHP1 variants, Fabry disease due to GLA variants, and autosomal-dominant tubulointerstitial kidney disease due to UMOD variants. Genetic diagnoses were not concordant with clinical diagnoses, except for patients with PKD1 variant. This largest study on genetic analysis in hemodialysis-dependent adults revealed the presence of undiagnosed inherited kidney diseases.

Unraveling the conformational dynamics of UMOD protein variants in autosomal dominant tubulointerstitial kidney disease: Insights from molecular dynamics simulations

Unraveling the conformational dynamics of UMOD protein variants in autosomal dominant tubulointerstitial kidney disease: Insights from molecular dynamics simulations

Autosomal Dominant Tubulointerstitial Kidney Disease Case with Sever Acute Kidney Injury in Activities Beyond the Usual: An Unusual Presentation of the Disease

Introduction: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is associated with multiple gene mutations and is recognized under various names, including medullary cystic kidney disease type 2, familial juvenile hyperuricemic nephropathy, uromodulin-associated kidney disease, and medullary cystic kidney disease type 2. A comprehensive understanding of these rare disorders can shed light on the pattern of tubulointerstitial fibrosis observed in various forms of chronic kidney disease. Case Presentation: Here, a case of a patient is presented who experienced acute kidney injury (AKI) following severe physical activity and an atypical manifestation of this genetic disorder. Typically, ADTKD leads to a gradual loss of kidney function, but the patient presented with AKI. The patient's renal function returned to normal following appropriate therapy. The patient's brother had a similar history of renal disease following physical activities, prompting suspicion of a shared genetic disorder. Conclusions: A genome-wide association study (GWAS) was conducted, and the results revealed the presence of the mucin 1 (MUC1) mutation, confirming the diagnosis of ADTKD. This case highlights the importance of recognizing atypical presentations of genetic disorders and utilizing advanced genetic studies for accurate diagnosis and management.

Development of steroid-resistant nephrotic syndrome in a child with CAKUT

Introduction: One of the congenital anomalies of the kidneys and urinary tracts (CAKUT) is renal hypodysplasia/aplasia type 3 (PHDA3), caused by pathogenic variants in the GREB1L gene not associated with steroid-resistant nephrotic syndrome (SRNS). PGDA3 leads to chronic kidney disease (CKD). Variants in the UMOD gene associated with autosomal dominant tubulointerstitial kidney disease (ATKD-UMOD) also lead to CKD. The association of the GREB1L/UMOD genes with SRNS has not been previously described. Purpose of the article: To demonstrate a rare clinical case of SRNS in a child with CAKUT. Patients and methods: A patient with CAKUT in the form of PGDA3 and ADTBP-UMOD is observed in the department of nephrology for 2 years. Post-infectious development of SRNS required a revision of the genetic screening. Results: On the whole-genome sequencing were found a variability in the genes that cause CAKUT, with no candidate genes for SRNS. Conclusion: The described case stands out with clinical polymorphism of CAKUT and the variability of UMOD and GREB1L gene variants not associated with the development of SRNS. Infectious etiology of the development of SRNS is assumed. The patient has an intensive development of CKD stage 4, requiring a long-term follow-up in dynamics.

The Pathophysiology of Inherited Renal Cystic Diseases.

Renal cystic diseases (RCDs) can arise from utero to early adulthood and present with a variety of symptoms including renal, hepatic, and cardiovascular manifestations. It is well known that common RCDs such as autosomal polycystic kidney disease and autosomal recessive kidney disease are linked to genes such as PKD1 and PKHD1, respectively. However, it is important to investigate the genetic pathophysiology of how these gene mutations lead to clinical symptoms and include some of the less-studied RCDs, such as autosomal dominant tubulointerstitial kidney disease, multicystic dysplastic kidney, Zellweger syndrome, calyceal diverticula, and more. We plan to take a thorough look into the genetic involvement and clinical sequalae of a number of RCDs with the goal of helping to guide diagnosis, counseling, and treatment.

Autosomal dominant ApoA4 mutations present as tubulointerstitial kidney disease with medullary amyloidosis

Sporadic cases of apolipoprotein A-IV medullary amyloidosis have been reported. Here we describe five families found to have autosomal dominant medullary amyloidosis due to two different pathogenic APOA4 variants. A large family with autosomal dominant chronic kidney disease (CKD) and bland urinary sediment underwent whole genome sequencing with identification of a chr11:116692578 G>C (hg19) variant encoding the missense mutation p.L66V of the ApoA4 protein. We identified two other distantly related families from our registry with the same variant and two other distantly related families with a chr11:116693454 C>T (hg19) variant encoding the missense mutation p.D33N. Both mutations are unique to affected families, evolutionarily conserved and predicted to expand the amyloidogenic hotspot in the ApoA4 structure. Clinically affected individuals suffered from CKD with a bland urinary sediment and a mean age for kidney failure of 64.5 years. Genotyping identified 48 genetically affected individuals; 44 individuals had an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73 m2, including all 25 individuals with kidney failure. Significantly, 11 of 14 genetically unaffected individuals had an eGFR over 60 ml/min/1.73 m2. Fifteen genetically affected individuals presented with higher plasma ApoA4 concentrations. Kidney pathologic specimens from four individuals revealed amyloid deposits limited to the medulla, with the mutated ApoA4 identified by mass-spectrometry as the predominant amyloid constituent in all three available biopsies. Thus, ApoA4 mutations can cause autosomal dominant medullary amyloidosis, with marked amyloid deposition limited to the kidney medulla and presenting with autosomal dominant CKD with a bland urinary sediment. Diagnosis relies on a careful family history, APOA4 sequencing and pathologic studies.

Development of steroid-resistant nephrotic syndrome in a child with CAKUT-syndrome

BACKGROUND. One of the congenital anomalies of the kidneys and urinary tracts (CAKUT) is renal hypodysplasia/aplasia type 3 (PHDA3), caused by pathogenic variants in the GREB1L gene not associated with steroid-resistant nephrotic syndrome (SRNS). PGDA3 leads to chronic kidney disease (CKD). Variants in the UMOD gene associated with autosomal dominant tubulointerstitial kidney disease (ATKD-UMOD) also lead to CKD. The association of the GREB1L/UMOD genes with SRNS has not been previously described.THE AIM: to demonstrate a rare clinical case of SRNS in a child with CAKUT-syndrome.PATIENTS AND METHODS. A patient with CAKUT in the form of PGDA3 and ADTBP-UMOD is observed in the department of nephrology for 2 years. Post-infectious development of SRNS required a revision of the genetic screening.RESULTS. On the whole-genome sequencing were found a variability in the genes that cause CAKUT, with no candidate genes for SRNS.CONCLUSION. The described case stands out with clinical polymorphism of CAKUT and the variability of UMOD and GREB1L gene variants not associated with the development of SRNS. Infectious etiology of the development of SRNS is assumed. The patient has an intensive development of CKD stage 4, requiring a long-term follow-up in dynamics.

Dissecting Heterogeneity and Common Pathogenetic Pathways in Autosomal Dominant Tubulointerstitial Kidney Disease due to Mutations in REN

Dissecting Heterogeneity and Common Pathogenetic Pathways in Autosomal Dominant Tubulointerstitial Kidney Disease due to Mutations in REN

Allelic effects on uromodulin aggregates drive autosomal dominant tubulointerstitial kidney disease

Missense mutations in the uromodulin (UMOD) gene cause autosomal dominant tubulointerstitial kidney disease (ADTKD), one of the most common monogenic kidney diseases. The unknown impact of the allelic and gene dosage effects and fate of mutant uromodulin leaves open the gap between postulated gain‐of‐function mutations, end‐organ damage and disease progression in ADTKD. Based on two prevalent missense UMOD mutations with divergent disease progression, we generated UmodC171Y and UmodR186S knock‐in mice that showed strong allelic and gene dosage effects on uromodulin aggregates and activation of ER stress and unfolded protein and immune responses, leading to variable kidney damage. Deletion of the wild‐type Umod allele in heterozygous UmodR186S mice increased the formation of uromodulin aggregates and ER stress. Studies in kidney tubular cells confirmed differences in uromodulin aggregates, with activation of mutation‐specific quality control and clearance mechanisms. Enhancement of autophagy by starvation and mTORC1 inhibition decreased uromodulin aggregates. These studies substantiate the role of toxic aggregates as driving progression of ADTKD‐UMOD, relevant for therapeutic strategies to improve clearance of mutant uromodulin.

MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice

Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD), a leading hereditary kidney disease. There are no targeted therapies. In our generated mouse model recapitulating human ADTKD-UMOD carrying a leading UMOD mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are impaired, leading to cGAS-STING activation and tubular injury. Moreover, we demonstrate that inducible tubular overexpression of mesencephalic astrocyte-derived neurotrophic factor (MANF), a secreted endoplasmic reticulum protein, after the onset of disease stimulates autophagy/mitophagy, clears mutant UMOD, and promotes mitochondrial biogenesis through p-AMPK enhancement, thus protecting kidney function in our ADTKD mouse model. Conversely, genetic ablation of MANF in the mutant thick ascending limb tubular cells worsens autophagy suppression and kidney fibrosis. Together, we have discovered MANF as a biotherapeutic protein and elucidated previously unknown mechanisms of MANF in the regulation of organelle homeostasis, which may have broad therapeutic applications to treat various proteinopathies.

A Role for Genetic Modifiers in Tubulointerstitial Kidney Diseases.

With the increased availability of genomic sequencing technologies, the molecular bases for kidney diseases such as nephronophthisis and mitochondrially inherited and autosomal-dominant tubulointerstitial kidney diseases (ADTKD) has become increasingly apparent. These tubulointerstitial kidney diseases (TKD) are monogenic diseases of the tubulointerstitium and result in interstitial fibrosis and tubular atrophy (IF/TA). However, monogenic inheritance alone does not adequately explain the highly variable onset of kidney failure and extra-renal manifestations. Phenotypes vary considerably between individuals harbouring the same pathogenic variant in the same putative monogenic gene, even within families sharing common environmental factors. While the extreme end of the disease spectrum may have dramatic syndromic manifestations typically diagnosed in childhood, many patients present a more subtle phenotype with little to differentiate them from many other common forms of non-proteinuric chronic kidney disease (CKD). This review summarises the expanding repertoire of genes underpinning TKD and their known phenotypic manifestations. Furthermore, we collate the growing evidence for a role of modifier genes and discuss the extent to which these data bridge the historical gap between apparently rare monogenic TKD and polygenic non-proteinuric CKD (excluding polycystic kidney disease).

Computational investigation of a novel uromodulin gene mutation (p.Y286C) in a family with autosomal dominant tubulointerstitial renal disease: A case study

Autosomal dominant tubulointerstitial kidney disease caused by a pathogenic variant in the UMOD gene (ADTKD) is a rare tubulointerstitial nephropathy characterized by hyperuricemia, gout, and slowly-progressing chronic renal insufficiency. The disease invariably progresses to end-stage renal disease (ESRD), and is believed to be one of the most common monogenic forms of kidney disease. It presents complete penetrance and inter- and intrafamilial clinical heterogeneity. The index case is a 17-year-old female who, at the age of seven began her renal function evaluation due to a family history of chronic renal insufficiency without etiological diagnosis. At this time she was already presenting with joint pain and increased serum creatinine and uric acid. Genetic testing detected a heterozygous variation in UMOD gene, c.857 A>G; p.Y286C, in two tested affected individuals but not in an unaffected family member. Here, an in silico analysis of the impact of this variant was performed, which provided support as to the deleterious nature of the variant. We also described clinical and laboratory data of 6 affected members, whose age of ESRD showed high variability, in agreement with the literature. This case provides evidence of the pathogenicity of a novel variant detected in the UMOD gene, in addition to providing clinical and laboratory data of individuals carrying this variant, highlighting the intrafamilial clinical variability.

Recurrent UMOD Mutations in Australian Families with Autosomal Dominant Tubulointerstitial Kidney Disease: A Possible Founder Effect?

Recurrent UMOD Mutations in Australian Families with Autosomal Dominant Tubulointerstitial Kidney Disease: A Possible Founder Effect?

Recurrent UMOD Mutations in Australian Families with Autosomal Dominant Tubulointerstitial Kidney Disease: A Possible Founder Effect?

Recurrent UMOD Mutations in Australian Families with Autosomal Dominant Tubulointerstitial Kidney Disease: A Possible Founder Effect?

Autosomal dominant tubulointerstitial kidney disease: Diagnostic challenges in the absence of genetic testing. A case report

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a group of rare uncommon genetic disorders characterized by tubular damage and interstitial fibrosis in the absence of glomerular lesions. It has autosomal dominant inheritance and inevitable progression to end-stage kidney disease (ESKD). In nephrological practice, we usually face glomerular diseases that have well-recognized symptoms. Therefore, when we see a patient with impaired kidney function but without any signs of glomerular disease, it is always more challenging to discover the reason for it. The present case illustrates tubulointerstitial lesions due to possible genetic reasons. A 38-year-old non-hypertensive female presented with impaired renal function, a family history of CKD, proteinuria 0,5 g/day, and urinary sediment unremarkable. Relying on her family history, the middle age of onset, the progression to the end-stage kidney disease, and laboratory and histological results, an autosomal dominant tubulointerstitial kidney disease was suspected. Initially, diagnosed tubulointerstitial kidney disease is likely to be secondary to a mutation in genes encoding mucin-1. Pathology findings in this case played a pivotal role in establishing the diagnosis. However, it still needs to be proven by genetic tests. The purpose of this manuscript was to summarize the case of ADTKD, discuss the challenges in diagnosing ADTKD without genetic testing, and emphasize the importance of genetic testing in confirming the diagnosis.

Dnajb11-Kidney Disease Develops from Reduced Polycystin-1 Dosage but not Unfolded Protein Response in Mice.

Heterozygous DNAJB11 mutation carriers manifest with small cystic kidneys and renal failure in adulthood. Recessive cases with prenatal cystic kidney dysplasia were recently described. Our in vitro and mouse model studies investigate the proposed disease mechanism as an overlap of autosomal-dominant polycystic kidney disease and autosomal-dominant tubulointerstitial kidney disease pathogenesis. We find that DNAJB11 loss impairs cleavage and maturation of the autosomal-dominant polycystic kidney disease protein polycystin-1 (PC1) and results in dosage-dependent cyst formation in mice. We find that Dnajb11 loss does not activate the unfolded protein response, drawing a fundamental contrast with the pathogenesis of autosomal-dominant tubulointerstitial kidney disease. We instead propose that fibrosis in DNAJB11 -kidney disease may represent an exaggerated response to polycystin-dependent cysts. Patients with heterozygous inactivating mutations in DNAJB11 manifest with cystic but not enlarged kidneys and renal failure in adulthood. Pathogenesis is proposed to resemble an overlap of autosomal-dominant polycystic kidney disease (ADPKD) and autosomal-dominant tubulointerstitial kidney disease (ADTKD), but this phenotype has never been modeled in vivo . DNAJB11 encodes an Hsp40 cochaperone in the endoplasmic reticulum: the site of maturation of the ADPKD polycystin-1 (PC1) protein and of unfolded protein response (UPR) activation in ADTKD. We hypothesized that investigation of DNAJB11 would shed light on mechanisms for both diseases. We used germline and conditional alleles to model Dnajb11 -kidney disease in mice. In complementary experiments, we generated two novel Dnajb11-/- cell lines that allow assessment of PC1 C-terminal fragment and its ratio to the immature full-length protein. Dnajb11 loss results in a profound defect in PC1 cleavage but with no effect on other cystoproteins assayed. Dnajb11-/- mice are live-born at below the expected Mendelian ratio and die at a weaning age with cystic kidneys. Conditional loss of Dnajb11 in renal tubular epithelium results in PC1 dosage-dependent kidney cysts, thus defining a shared mechanism with ADPKD. Dnajb11 mouse models show no evidence of UPR activation or cyst-independent fibrosis, which is a fundamental distinction from typical ADTKD pathogenesis. DNAJB11 -kidney disease is on the spectrum of ADPKD phenotypes with a PC1-dependent pathomechanism. The absence of UPR across multiple models suggests that alternative mechanisms, which may be cyst-dependent, explain the renal failure in the absence of kidney enlargement.

Hypoxia controls expression of kidney-pathogenic MUC1 variants.

The interplay between genetic and environmental factors influences the course of chronic kidney disease (CKD). In this context, genetic alterations in the kidney disease gene MUC1 (Mucin1) predispose to the development of CKD. These variations comprise the polymorphism rs4072037, which alters splicing of MUC1 mRNA, the length of a region with variable number of tandem repeats (VNTR), and rare autosomal-dominant inherited dominant-negative mutations in or 5' to the VNTR that causes autosomal dominant tubulointerstitial kidney disease (ADTKD-MUC1). As hypoxia plays a pivotal role in states of acute and chronic kidney injury, we explored the effects of hypoxia-inducible transcription factors (HIF) on the expression of MUC1 and its pathogenic variants in isolated primary human renal tubular cells. We defined a HIF-binding DNA regulatory element in the promoter-proximal region of MUC1 from which hypoxia or treatment with HIF stabilizers, which were recently approved for an anti-anemic therapy in CKD patients, increased levels of wild-type MUC1 and the disease-associated variants. Thus, application of these compounds might exert unfavorable effects in patients carrying MUC1 risk variants.