Autosomal Dominant Tubulointerstitial Kidney Disease

Earn CME/CE in your profession:

Continuing Education Activity

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a group of inherited kidney disorders. It is usually characterized by progressive renal insufficiency, tubulointerstitial nephropathy, and bland urinary sediment. This condition is inherited by autosomal dominant manner. To avoid the high morbidity and mortality associated with this condition, it must be promptly diagnosed and treated. This activity describes the etiology, evaluation, and treatment of autosomal dominant tubulointerstitial kidney disease and highlights the role of the interprofessional team in evaluating and improving care for patients with this condition.


  • Identify the etiology of autosomal dominant tubulointerstitial kidney disease.
  • Describe the appropriate history and evaluation of autosomal dominant tubulointerstitial kidney disease.
  • Outline the management options available for autosomal dominant tubulointerstitial kidney disease.
  • Review interprofessional team strategies for improving care coordination and communication to advance autosomal dominant tubulointerstitial kidney disease and improve outcomes.


Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a group of inherited kidney disorders. It is usually characterized by progressive renal insufficiency, tubulointerstitial nephropathy, and bland urinary sediment. This condition is inherited by autosomal dominant manner. To date, many different gene mutations that cause ADTKD had been detected: uromodulin (UMOD), renin (REN), mucin-1 (MUC1), hepatocyte nuclear factor 1β (HNF1B), and recently SEC. 61A1 mutation was identified as a novel cause of this disease.[1] 

These genes encode different proteins, which are imperative for normal renal function. The clinical scenario is varied, non-specific, and it is dependent on the type of gene mutation. It is difficult to diagnose this condition because it is a rare and recently identified disorder that is not well known to most primary health care providers and nephrologists.[2]


Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare renal disorder caused by variable mutations in different genes. To date, at least five different gene mutations cause this disorder as follows: uromodulin (UMOD), mucin-1 (MUC1), renin (REN), hepatocyte nuclear factor 1β (HNF1B), and recently identified SEC61A1. An autosomal dominant inheritance pattern inherits this disorder. MUC1 gene encodes a mucin-1 protein, UMOD gene encodes uromodulin protein (previously known as Tamm-Horsfall protein), HNF1B gene encodes hepatocyte nuclear factor 1beta, REN gene encodes renin, SEC61A1 gene encodes translocon subunit SEC61A.[3]


Since the autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare and recently identified disorder, the exact prevalence has not been determined, neither in the United States of America nor worldwide.[3] There is no difference in the incidence rate between males and females because this condition is inherited in an autosomal dominant manner. The child, either male or female, has a fifty percent chance of inheriting the mutated gene. The mean age of end-stage kidney disease is 45 years old, but the range is variable, starting from 17 years old up to 75 years old.[4]


In autosomal dominant tubulointerstitial kidney disease-MUC1, the MUC1 gene is located on chromosome 1q21. It is thought that most MUC1 mutations are caused by cytosine duplication within a seven-cytosine stretch in the variable-number tandem repeats (VNTR) region that usually produces a frameshift mutation. This mutated gene produces an abnormal protein known as MUC1 frameshift protein (MUC1fs). Accumulation of this abnormal protein (MUC1fs) in the renal tubular epithelial cells may be considered an important pathogenic factor in the pathophysiology of ADTKD-MUC1; in addition to that, positive staining of (MUC1fs) in the urinary exfoliated cells and renal tubular epithelial cells could help to diagnose this condition.[1]

In autosomal dominant tubulointerstitial kidney disease-UMOD, endoplasmic reticulum stress may occur due to retention of the mutant uromodulin (mUMOD) protein inside the endoplasmic reticulum (ER) of tubular epithelial cells in the thick ascending limb of the renal tubules. This will lead to tubular cell death and chronic kidney failure. About two-thirds of the mutations that cause ADTKD-UMOD (mUMOD) involve cysteine residues, and there are no mutations reported resulting in loss of transcription or truncation. All these findings imply the important role of the mutant uromodulin (mUMOD) protein in the pathophysiology of the ADTKD-UMOD.[5]

In autosomal dominant tubulointerstitial kidney disease-SEC61A1this condition is associated with missense mutations in SEC61A1. It is responsible for the encoding of the alpha subunit of endoplasmatic reticular membrane translocon SEC61. Many studies confirmed that the normal function of the SEC61 complex and its translocon is essential for normal kidney development.[6]

In autosomal dominant tubulointerstitial kidney disease-REN, the disease is mainly caused by non-truncating mutations in the first exon of the REN gene that affect the protein leader peptide residues. The type of the mutation is either missense changes like (L16R, W10R, W17R, and C20R) or an in-frame deletion (L16del). In another study, a new novel renin mutation in exon 10 of the REN gene was identified. These mutations can lead to endoplasmic reticulum stress and unfolded protein response activation, leading to improper renal development.[7]

In autosomal dominant tubulointerstitial kidney disease-HNF1B, the HNF1B gene has an essential role in early embryonic development. It is also known as transcription factor-2 (TCF2). This gene is located on chromosome 17q12, which codes for protein hepatocyte nuclear factor 1 homeobox B. Since HNF1B is expressed in the body's variable tissues like the kidney, liver, pancreas, and genitourinary tract, this may explain the variable clinical presentations of the HNF1B-related disorders. It was found that loss of HNF1b could induce epithelial-mesenchymal transition. This type of transition will ultimately lead to kidney fibrosis by up-regulation of the expression of transforming growth factor−β ligands in renal epithelial cells.[8]

History and Physical

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a group of inherited kidney disorders caused by different gene mutations that share the same histological findings. The clinical manifestations are widely variable and gene-dependent. The followings encompass the most likely observed clinical features for each gene mutation:

ADTKD-MUC1 related was previously called medullary cystic kidney disease type 1. This disease is characterized by progressive tubulointerstitial fibrosis that ultimately leads to end-stage kidney disease (ESKD). ESKD typically started in adulthood, but it may occur at any age from 20 years old to 70 years old. There are no other systemic manifestations. Since this disease is transmitted in an autosomal dominant manner, a family history of chronic renal insufficiency is an important key point to figure out this disease.[9]

ADTKD-UMOD related was known historically as familial juvenile hyperuricemic nephropathy type 1 (FJHN1), uromodulin-associated kidney disease (UMOD-associated kidney disease), and medullary cystic kidney disease type 2 (MCKD2). The clinical manifestation is slowly progressive chronic renal failure, usually noticed in the teen years and progresses to end-stage kidney disease (ESKD) between the fourth and seventh decades of life. Other important clinical features are gout and hyperuricemia, resulting from inappropriately decreased fractional urate excretion that usually occurs as early as the teenage years.[10]

ADTKD-REN related was known previously as familial juvenile hyperuricemic nephropathy type 2 (FJHN2). This disease is characterized by hypo-proliferative anemia with a low hemoglobin concentration in the first decade of life. The clinical symptoms of chronic kidney disease (CKD) and hyperuricemia start in childhood or adolescence. This condition is also characterized by bland urinary sediment, mildly elevated serum potassium concentration, slightly decreased blood pressure, polyuria, low plasma renin activity. Patients usually progress to end-stage kidney disease (ESKD) in their fourth to sixth decade of life.[7]

ADTKD-SEC61A1 related is a newly discovered disease caused by a mutation in SEC61A1. Since it is a new disease, the whole clinical picture is not conspicuous. To date, very few families have been identified with this disorder. In one family, dysplastic kidneys, anemia and, intrauterine growth retardation were present. In another family, anemia, neutropenia with abscess formation, and chronic kidney disease were documented.[4]

ADTKD-HNF1B related is caused by a mutation in the TCF2 gene. The homeodomain-containing transcription factors, hepatocyte nuclear factor 1 alpha, and 1 beta are expressed both in the kidney and the pancreas. It has been identified that mutations in this gene may cause the maturity-onset diabetes of youth (MODY), but further studies explicate that mutations in this gene may also lead to renal manifestations. The varied clinical manifestations and the fact that these clinical manifestations are not present consistently in all affected family members made the diagnosis of this condition difficult. The non-renal manifestations may include the maturity-onset diabetes of youth, abnormal liver function test of unclear etiology, genito-urinary tract malformations, hyperuricemia with gout in adolescence hypomagnesemia may occur in some individuals. The renal manifestations are common in adulthood and often involve numerous renal cysts, congenital solitary kidney, congenital anomalies of the kidney and urinary tract system, renal dysplasia, and hypoplastic kidneys.[11][4]


Since it is a rare condition and difficult to predict, it is prudent for the health care providers to raise the suspicion about this disease, especially if the patient presented with signs and symptoms of renal failure at a young age with a family history of end-stage renal disease.

It is known that autosomal dominant tubulointerstitial kidney disease (ADTKD) is a group of inherited kidney disorders caused by different types of gene mutations with varied clinical presentations. The rarity of the disease and the limited knowledge made this condition under-diagnosed for many years. Even with limited knowledge, nephrologists can easily obtain the diagnosis and improve patient care if they take the three cardinal features of this condition in their consideration while making the diagnosis. The three cardinal features of this condition:

  1. These conditions are inherited in an autosomal dominant method and should always be considered whenever both a child and parent suffer from kidney disease; the presence of more affected family members provides more support.
  2. These conditions are characterized by bland urinary sediment, ruling out the disease's glomerular origin.
  3. The variable rate of decline in renal function with the mean age of end-stage renal disease is approximately 45 years, but the range is 17 years up to 75 years.[4]

In ADTKD-MUC1, the genetic diagnosis is not easy and straightforward. It is essential to know that testing for the MUC1 gene mutation is not a direct mutational analysis, and this test is not performed at commercial clinical laboratories at this time. A recent study was performed to detect MUC1fs protein by immunostaining the MUC1fs protein on the epithelial tissues and the urinary cell smears in individuals with ADTKD-MUC1, and the result is promising. Still, it is not readily available at the clinical lab yet.[12]

In ADTKD-UMOD, the diagnosis may be made based on the appropriate, relevant clinical scenario in addition to the knowledge that another family member has been identified with a UMOD mutation on genetic testing. However, uromodulin genetic analysis is readily available at commercial clinical laboratories.[10]

In ADTKD-REN, genetic analysis of the REN gene should always be used to make the diagnosis. When the renin and aldosterone are stimulated, the levels are in the low normal range in most patients, making this type of measurement inadequate for making the diagnosis.[4]

In ADTKD-HNF1B, this condition's clinical scenario is widely variable, with different renal and extra-renal clinical manifestations. The cost-effective NGS-based strategies allow rapid and simultaneous sequencing of several genes, including HNF1B.[8]

In ADTKD-SEC61A1, very few families have been diagnosed with this condition. Currently, the diagnostic criteria are still under development.

Treatment / Management

Treatment of autosomal dominant tubulointerstitial kidney disease (ADTKD) mainly focuses on managing the symptoms associated with each type of the disease and slow down the progression to end-stage renal disease. The followings are the most important management options for each sub-type of the disease:

Regarding ADTKD-UMOD, allopurinol or febuxostat are the best treatment options to treat gout and hyperuricemia. To prevent further gout attacks and gouty tophi, patients should be encouraged to take one of these medications as soon as gout developed. Although starting allopurinol early in life may prevent gout from developing later, the risk and benefit should be discussed thoroughly with the patient or the family if the patient is minor because allopurinol has some important side effect, severe allergic reaction.[13] It is also important to inform all women of child-bearing age that this medication may have some teratogenic effects and should be stopped before the pregnancy.[14] As kidney disease progression is typically slow, and the UMOD mutations affect only the kidneys, these patients are excellent renal transplantation candidates. 

Regarding ADTKD-MUC1, there is no specific therapy at present. Optimal therapy to manage chronic kidney disease like controlling blood pressure and secondary chronic renal failure changes are the only available treatments for this condition. As progression to end-stage kidney disease is at a slow rate, and the fact that this condition affects only the kidney, these patients are excellent candidates for renal transplantation.[4]

For ADTKD-REN, there are several treatment options currently available. As these patients are in mild hypovolemia with a low renin state, it is essential to avoid the low sodium diet, commonly recommended in chronic kidney disease. These patients are prone to develop acute kidney injury on a low sodium diet due to worsening hypotension. Hyperkalemia and mild hypotension could be treated by fludrocortisone or a higher sodium content diet. Fludrocortisone may correct the hyperkalemia, hypotension and improve the hyperuricemia but does not ameliorate the hemoglobin levels. Fludrocortisone may slow chronic kidney disease progression by lowering renin production (both the normal and the mutated renin).[4]

For ADTKD-HNF1B, there is no specific therapy for this disease. The treatment is mainly supportive of chronic kidney disease. Allopurinol or febuxostat should be considered for patients with early-onset gout to prevent tophus development and urate accumulation. Screening for abnormal liver function tests, hyperglycemia, hypomagnesemia, and hyperuricemia is an essential part of the management to prevent further complications. To evaluate the renal morphologic abnormalities, renal ultrasound should be performed.[15][4]

Regarding ADTKD-SEC61A1, there is no specific therapy to treat the underlying cause, but managing the associated congenital anemia and preventing the opportunistic infection should be carried out for a better prognosis.

It is important to know that patients with ADTKD are excellent candidates for kidney transplantation, particularly if there are no extra-renal manifestations.[4]

Differential Diagnosis

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a congenital renal anomaly that ultimately leads to end-stage kidney disease. This condition is inherited in an autosomal dominant manner. It is essential to exclude other congenital renal diseases before making the diagnosis. The following consists of the most likely differential diagnosis of this condition:[9][10]

  • Early-onset autosomal dominant polycystic kidney disease
  • Autosomal recessive polycystic kidney disease
  • Urinary tract obstruction
  • Renal dysplasia
  • Gout


Although autosomal dominant tubulointerstitial kidney disease (ADTKD) is considered a benign condition, most cases will ultimately develop end-stage kidney disease. To improve the prognosis, the treatment should be focused on slowing down the progression to end-stage kidney disease (ESKD). The mean age at which the ESKD is developed is variable, and it depends on the form of the disease; it could be at a younger age, as in the teens, or later in older adulthood. Lifelong treatment could control the symptoms associated with chronic kidney disease, but it will not treat the underlying cause. It was documented that renal transplantation may have an excellent prognosis, especially if the kidney is the only organ affected.[4][13]


End-stage kidney disease (ESKD) is the most important complication associated with this condition. ESKD leads to variable health issues that should be addressed thoroughly and treated properly. The followings encompass the most likely complications associated with ESKD:[4][13] 

  • Anemia 
  • Osteoporosis and fracture
  • Platelet dysfunction with easy bruising
  • Congestive heart failure
  • Pericarditis
  • Menstrual problems and infertility
  • Hypertension
  • Peripheral neuropathy
  • Hyperkalemia and cardiac arrest

In addition to the complications associated with ESKD, each form of this disease has certain complications that should be addressed as well to improve the patient quality of life as the following: 

  • ADTKD-UMOD is associated with hyperuricemia and gout
  • ADTKD-REN is associated with hypo-proliferative anemia, hyperuricemia, mild hypotension, mild hyperkalemia
  • ADTKD-HNF1B is associated with maturity-onset diabetes of youth, abnormal liver function test of unclear etiology, genito-urinary tract malformations, hyperuricemia with gout, and hypomagnesemia
  • ADTKD-SEC61A1 is associated with anemia, neutropenia with abscess formation


The management of autosomal dominant tubulointerstitial kidney disease (ADTKD) and its complications require a multidisciplinary team consisting of

  • Nephrologist
  • Hepatologist
  • Cardiologist
  • Hematologist

Deterrence and Patient Education

Patients with autosomal dominant tubulointerstitial kidney disease (ADTKD) should be informed about this disease's congenital nature. Health professionals should clarify that there are no available medications that can treat the underlying cause. The management plan should focus on preventive measures to slow down the progression to end-stage kidney disease (ESKD) and relieve the symptoms associated with each form of the disease. Health care providers also have to advise patients about the importance of medication adherence and compliance. Since this condition is transmitted by autosomal dominant manner, other family members are likely to be affected by this condition even if they are asymptomatic, so screening for genetic mutations in the affected family members is rational.[4]

Enhancing Healthcare Team Outcomes

The management of this condition requires the collaboration of the entire healthcare team. The primary healthcare provider should be aware of this condition, especially if the patient presented a progressive decline in renal function associated with bland urinary sediment. These patients should be referred to the nephrologist to manage the renal insufficiency and prepare them for renal transplantation if mandatory. If it is confirmed that the patient carries the mutated gene, other family members should be screened for that mutation as their probability to be affected high, and early screening could improve the prognosis and outcomes.

Article Details

Article Author

Younus M. Shamam

Article Editor:

Muhammad F. Hashmi


4/16/2022 12:38:27 AM



Wang GQ,Rui HL,Dong HR,Sun LJ,Yang M,Wang YY,Ye N,Zhao ZR,Liu XJ,Xu XY,Chen YP,Cheng H, SMRT sequencing revealed to be an effective method for ADTKD-MUC1 diagnosis through follow-up analysis of a Chinese family. Scientific reports. 2020 May 25     [PubMed PMID: 32451462]


Devuyst O,Olinger E,Weber S,Eckardt KU,Kmoch S,Rampoldi L,Bleyer AJ, Autosomal dominant tubulointerstitial kidney disease. Nature reviews. Disease primers. 2019 Sep 5     [PubMed PMID: 31488840]


Cormican S,Connaughton DM,Kennedy C,Murray S,Živná M,Kmoch S,Fennelly NK,O'Kelly P,Benson KA,Conlon ET,Cavalleri G,Foley C,Doyle B,Dorman A,Little MA,Lavin P,Kidd K,Bleyer AJ,Conlon PJ, Autosomal dominant tubulointerstitial kidney disease (ADTKD) in Ireland. Renal failure. 2019 Nov     [PubMed PMID: 31509055]


Ectopic pregnancy following tubal sterilizations., Athari TA,Ravangard F,, The West Virginia medical journal, 1978 Sep     [PubMed PMID: 32954071]


Continuing medical education in West Virginia., Smith RL,, The West Virginia medical journal, 1978 Sep     [PubMed PMID: 27392076]


Schaeffer C,Izzi C,Vettori A,Pasqualetto E,Cittaro D,Lazarevic D,Caridi G,Gnutti B,Mazza C,Jovine L,Scolari F,Rampoldi L, Autosomal Dominant Tubulointerstitial Kidney Disease with Adult Onset due to a Novel Renin Mutation Mapping in the Mature Protein. Scientific reports. 2019 Aug 12     [PubMed PMID: 31406136]


Izzi C,Dordoni C,Econimo L,Delbarba E,Grati FR,Martin E,Mazza C,Savoldi G,Rampoldi L,Alberici F,Scolari F, Variable Expressivity of HNF1B Nephropathy, From Renal Cysts and Diabetes to Medullary Sponge Kidney Through Tubulo-interstitial Kidney Disease. Kidney international reports. 2020 Dec     [PubMed PMID: 33305128]


Bleyer AJ,Kmoch S,Adam MP,Ardinger HH,Pagon RA,Wallace SE,Bean LJH,Mirzaa G,Amemiya A, Autosomal Dominant Tubulointerstitial Kidney Disease, {i}MUC1{/i}-Related GeneReviews<sup>®</sup>. 1993     [PubMed PMID: 23946964]


[New ways for a dental service. A discussion with dental students]., Dreher J,, Zahnarzteblatt Baden-Wurttemberg, 1978 Apr     [PubMed PMID: 26319241]


Eckardt KU,Alper SL,Antignac C,Bleyer AJ,Chauveau D,Dahan K,Deltas C,Hosking A,Kmoch S,Rampoldi L,Wiesener M,Wolf MT,Devuyst O,Kidney Disease: Improving Global Outcomes., Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management--A KDIGO consensus report. Kidney international. 2015 Oct     [PubMed PMID: 25738250]


Hoeltzenbein M,Stieler K,Panse M,Wacker E,Schaefer C, Allopurinol Use during Pregnancy - Outcome of 31 Prospectively Ascertained Cases and a Phenotype Possibly Indicative for Teratogenicity. PloS one. 2013     [PubMed PMID: 23840514]


Faguer S,Chassaing N,Bandin F,Prouheze C,Garnier A,Casemayou A,Huart A,Schanstra JP,Calvas P,Decramer S,Chauveau D, The HNF1B score is a simple tool to select patients for HNF1B gene analysis. Kidney international. 2014 Nov     [PubMed PMID: 24897035]