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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="StatPearls [Internet]" /><meta name="citation_title" content="Autosomal Dominant Tubulointerstitial Kidney Disease" /><meta name="citation_publisher" content="StatPearls Publishing" /><meta name="citation_date" content="2023/06/26" /><meta name="citation_author" content="Younus M. Shamam" /><meta name="citation_author" content="Muhammad F. Hashmi" /><meta name="citation_pmid" content="33760469" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK568710/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Autosomal Dominant Tubulointerstitial Kidney Disease" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="StatPearls Publishing" /><meta name="DC.Contributor" content="Younus M. Shamam" /><meta name="DC.Contributor" content="Muhammad F. Hashmi" /><meta name="DC.Date" content="2023/06/26" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK568710/" /><meta name="description" content="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. Multiple names have been suggested for this group of disorders, including ‘familial juvenile hyperuricemic nephropathy (FJHN),’ ‘medullary cystic kidney disease (MCKD) type 2’, ‘uromodulin-associated kidney disease (UAKD),’ UMOD-related diseases, and ‘MCKD type 1’. However, the variety of these names, and the idea that cysts are not pathognomonic, generates confusion. Kidney Disease: Improving Global Outcomes (KDIGO) suggests the adoption of new terminology for these diseases using a single name ‘autosomal dominant tubulointerstitial kidney disease’ (ADTKD) adjoining a gene-based subclassification and diagnostic criteria. These recommendations are anticipated to bring about homogeneity in the characterization of this monogenic group of diseases." /><meta name="og:title" content="Autosomal Dominant Tubulointerstitial Kidney Disease" /><meta name="og:type" content="book" /><meta name="og:description" content="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. Multiple names have been suggested for this group of disorders, including ‘familial juvenile hyperuricemic nephropathy (FJHN),’ ‘medullary cystic kidney disease (MCKD) type 2’, ‘uromodulin-associated kidney disease (UAKD),’ UMOD-related diseases, and ‘MCKD type 1’. However, the variety of these names, and the idea that cysts are not pathognomonic, generates confusion. Kidney Disease: Improving Global Outcomes (KDIGO) suggests the adoption of new terminology for these diseases using a single name ‘autosomal dominant tubulointerstitial kidney disease’ (ADTKD) adjoining a gene-based subclassification and diagnostic criteria. These recommendations are anticipated to bring about homogeneity in the characterization of this monogenic group of diseases." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK568710/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-statpearls-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/statpearls/article-24904/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK568710/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} </style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script>
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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. </p></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK568710_"><span class="title" itemprop="name">Autosomal Dominant Tubulointerstitial Kidney Disease</span></h1><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Younus M. Shamam</span><sup>1</sup>; <span itemprop="author">Muhammad F. Hashmi</span><sup>2</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup> University of Mosul, College of Medicine , Mosul Iraq</div><div class="affiliation"><sup>2</sup> National Health Service</div><p class="small">Last Update: <span itemprop="dateModified">June 26, 2023</span>.</p></div><div class="body-content whole_rhythm" itemprop="text"><div id="article-24904.s1"><h2 id="_article-24904_s1_">Continuing Education Activity</h2><p>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 in an autosomal dominant manner. It must be promptly diagnosed and treated to avoid the high morbidity and mortality associated with this condition. 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.</p><p>
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<b>Objectives:</b>
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<ul><li class="half_rhythm"><div>Identify the etiology of autosomal dominant tubulointerstitial kidney disease.</div></li><li class="half_rhythm"><div>Describe the appropriate evaluation of autosomal dominant tubulointerstitial kidney disease.</div></li><li class="half_rhythm"><div>Outline the management options available for autosomal dominant tubulointerstitial kidney disease.</div></li><li class="half_rhythm"><div>Review interprofessional team strategies for improving care coordination and communication to advance autosomal dominant tubulointerstitial kidney disease and improve outcomes.</div></li></ul>
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</p></div><div id="article-24904.s2"><h2 id="_article-24904_s2_">Introduction</h2><p>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. Multiple names have been suggested for this group of disorders, including ‘familial juvenile hyperuricemic nephropathy (FJHN),’ ‘medullary cystic kidney disease (MCKD) type 2’, ‘uromodulin-associated kidney disease (UAKD),’ UMOD-related diseases, and ‘MCKD type 1’. However, the variety of these names, and the idea that cysts are not pathognomonic, generates confusion. Kidney Disease: Improving Global Outcomes (KDIGO) suggests the adoption of new terminology for these diseases using a single name ‘autosomal dominant tubulointerstitial kidney disease’ (ADTKD) adjoining a gene-based subclassification and diagnostic criteria. These recommendations are anticipated to bring about homogeneity in the characterization of this monogenic group of diseases.</p><p>This condition is inherited in an autosomal dominant manner. To date, many different gene mutations that cause ADTKD have been detected, such as uromodulin (UMOD), renin (REN), mucin-1 (MUC1), hepatocyte nuclear factor 1β (HNF1B), and SEC. 61A1 mutations.<a class="bk_pop" href="#article-24904.r1">[1]</a><a class="bk_pop" href="#article-24904.r2">[2]</a> These genes encode different proteins, which are imperative for normal renal function. The clinical scenario is varied and non-specific, and it is dependent on the type of gene mutation. The clinical manifestation of diseases associated with mutations in MUC1, UMOD, and REN appears to be limited to the kidney; however, HNF1B mutations cause variable extrarenal manifestations.<a class="bk_pop" href="#article-24904.r3">[3]</a></p><p>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.<a class="bk_pop" href="#article-24904.r4">[4]</a></p></div><div id="article-24904.s3"><h2 id="_article-24904_s3_">Etiology</h2><p>Autosomal dominant tubulointerstitial kidney disease is a rare renal disorder caused by variable mutations in different genes. As discussed previously, at least five different gene mutations have been observed to result in this group of disorders. 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 1 beta, REN gene encodes renin, and SEC61A1 gene encodes translocon subunit SEC61A.<a class="bk_pop" href="#article-24904.r5">[5]</a> The details of the pathogenesis underlying these genetic mutations will be discussed in the pathophysiology section of this article.</p></div><div id="article-24904.s4"><h2 id="_article-24904_s4_">Epidemiology</h2><p>Since autosomal dominant tubulointerstitial kidney disease is a rare and recently identified disorder, the exact prevalence has not been determined, neither in the United States of America nor worldwide.<a class="bk_pop" href="#article-24904.r5">[5]</a> 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 sex, has a 50% chance of inheriting the mutated gene. The mean age of end-stage renal disease (ESRD) is 45 years old, but the range is variable, starting from 17 years old up to 75 years old.<a class="bk_pop" href="#article-24904.r6">[6]</a> No geographic or sex differences are reported.</p><p>ADTKD-UMOD may present in adolescence with gout; hyperuricemia is highly prevalent. Chronic kidney disease (CKD) is often diagnosed in late adolescence or early adulthood. ADTKD-REN could present with hyperkalemia, anemia, and CKD as early as infancy. ADTKD-MUC1 patients generally develop CKD in their early twenties. ADTKD-HNF1B could present with genitourinary abnormalities in childhood, gout or diabetes in the teenage years, and CKD in the third decade of life. Extrarenal abnormalities are also possible. All subtypes usually lead to progressive ESRD, occurring typically between 25 and 70 years of age, and those with gout experience its onset between the age range of 3 and 51 years.<a class="bk_pop" href="#article-24904.r7">[7]</a><a class="bk_pop" href="#article-24904.r8">[8]</a> For instance, a study in Ireland reported that ADTKD was the underlying cause of ESRD in at least 0.54% of patients.<a class="bk_pop" href="#article-24904.r5">[5]</a></p><p>ADTKD is believed to be one of the commonest monogenic forms of renal disease, and overall it accounts for around 5% of all monogenic causes of CKD.<a class="bk_pop" href="#article-24904.r9">[9]</a> The prevalence of the various types of ADTKD has not been widely studied; however, ADTKD-UMOD and ADTKD-MUC1 are perhaps more frequently encountered than ADTKD due to mutations in HNF1B or REN. In many studies, ADTKD-UMOD was the most common genetic kidney disease after ADPKD, with a population prevalence of 9 per million.<a class="bk_pop" href="#article-24904.r10">[10]</a></p></div><div id="article-24904.s5"><h2 id="_article-24904_s5_">Pathophysiology</h2><p>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 the MUC1 frameshift protein (MUC1fs). Accumulating 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, positive staining of (MUC1fs) in the urinary exfoliated cells and renal tubular epithelial cells could help to diagnose this condition.<a class="bk_pop" href="#article-24904.r1">[1]</a></p><p>In ADTKD-UMOD, endoplasmic reticulum stress may occur due to the 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, decreased cellular release, urinary excretion of the wild-type protein, and chronic kidney disease.<a class="bk_pop" href="#article-24904.r11">[11]</a><a class="bk_pop" href="#article-24904.r12">[12]</a> Additionally, the defective biogenesis and intracellular uromodulin transport affect the Na-K-2Cl cotransporter resulting in defective urinary concentration and mild volume depletion, secondarily increasing proximal reabsorption of uric acid, leading to hyperuricemia.<a class="bk_pop" href="#article-24904.r13">[13]</a><a class="bk_pop" href="#article-24904.r14">[14]</a> About two-thirds of the mutations that cause ADTKD-UMOD (mUMOD) involve cysteine residues, and no mutations are 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 ADTKD-UMOD.<a class="bk_pop" href="#article-24904.r15">[15]</a></p><p>In autosomal dominant tubulointerstitial kidney disease-SEC61A1, this condition is associated with missense mutations in SEC61A1. It is responsible for encoding 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.<a class="bk_pop" href="#article-24904.r16">[16]</a></p><p>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). Another study identified a new novel renin mutation in exon 10 of the REN gene. These mutations can lead to endoplasmic reticulum stress and unfolded protein response activation, leading to improper renal development.<a class="bk_pop" href="#article-24904.r17">[17]</a></p><p>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 transition will ultimately lead to kidney fibrosis by up-regulation of the expression of transforming growth factor−β ligands in renal epithelial cells.<a class="bk_pop" href="#article-24904.r18">[18]</a></p></div><div id="article-24904.s6"><h2 id="_article-24904_s6_">Histopathology</h2><p>Histology of autosomal dominant tubulointerstitial kidney disease shows interstitial fibrosis with normal glomeruli and tubular atrophy. Lamellation and thickening of tubular basement membranes are frequent findings.<a class="bk_pop" href="#article-24904.r3">[3]</a><a class="bk_pop" href="#article-24904.r19">[19]</a><a class="bk_pop" href="#article-24904.r7">[7]</a><a class="bk_pop" href="#article-24904.r20">[20]</a> Tubular dilatation could be seen, and tubular microcysts have been observed. Immunofluorescence for immunoglobulins and complement is negative. Electron microscopy provides little or no additional information; however, it may reveal the accumulation of mUMOD in the ER of thick ascending loop cells.<a class="bk_pop" href="#article-24904.r21">[21]</a> The following is the list of changes that have been reported in association with various types of ADTKD:</p><ul><li class="half_rhythm"><div>Interstitial fibrosis</div></li><li class="half_rhythm"><div>Tubular atrophy</div></li><li class="half_rhythm"><div>Thickening and lamellation of tubular basement membranes</div></li><li class="half_rhythm"><div>Possibly tubular dilatation (microcysts)</div></li><li class="half_rhythm"><div>Negative immunofluorescence for complement and immunoglobulins</div></li></ul></div><div id="article-24904.s7"><h2 id="_article-24904_s7_">History and Physical</h2><p>Autosomal dominant tubulointerstitial kidney disease is a group of inherited kidney disorders caused by different gene mutations that share the same histological findings. Occasionally, nephronophthisis may appear in young individuals with features suggestive of ADTKD; however, autosomal recessive inheritance differentiates it from ADTKD3.<a class="bk_pop" href="#article-24904.r22">[22]</a> The rate of decline of the estimated glomerular filtration rate is exceedingly variable in ADTKD-MUC1, ADTKD-UMOD, and ADTKD-HNF1B.<a class="bk_pop" href="#article-24904.r19">[19]</a><a class="bk_pop" href="#article-24904.r7">[7]</a> The urinary sediment is generally normal, but microhematuria can occasionally be seen. Proteinuria is either mild or completely absent. Glomerular involvement has been rarely found, such as in glomerulocystic disease and secondary focal segmental glomerulosclerosis.<a class="bk_pop" href="#article-24904.r23">[23]</a> The initially normal kidney size starts to decline with advancing disease. Patients generally have no history of hypertension preceding impaired renal function. With progression, blood pressure could increase, but typically only modestly.</p><p>The clinical manifestations are widely variable and gene-dependent. The following is a discussion that encompasses the most likely observed clinical features with each gene mutation:</p><p>ADTKD-MUC1 was previously called medullary cystic kidney disease type 1. This disease is characterized by progressive tubulointerstitial fibrosis that ultimately leads to ESRD. ESRD typically starts 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 figuring out this disease.<a class="bk_pop" href="#article-24904.r24">[24]</a></p><p>ADTKD-UMOD 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 kidney disease, usually noticed in the teen years, and progression to ESRD 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.<a class="bk_pop" href="#article-24904.r25">[25]</a></p><p>ADTKD-REN 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 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, and low plasma renin activity. Patients usually progress to ESRD in their fourth to sixth decade of life.<a class="bk_pop" href="#article-24904.r17">[17]</a></p><p>ADTKD-SEC61A1 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.<a class="bk_pop" href="#article-24904.r6">[6]</a></p><p>A mutation in the TCF2 gene causes ADTKD-HNF1B. The kidney and the pancreas express the homeodomain-containing transcription factors hepatocyte nuclear factor 1 alpha and 1 beta. Research has 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 diagnosing this condition difficult. The non-renal manifestations may include maturity-onset diabetes mellitus of the young, abnormal liver function tests of unclear etiology, genito-urinary tract malformations, and 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.<a class="bk_pop" href="#article-24904.r26">[26]</a><a class="bk_pop" href="#article-24904.r6">[6]</a></p></div><div id="article-24904.s8"><h2 id="_article-24904_s8_">Evaluation</h2><p>Since autosomal dominant tubulointerstitial kidney disease is a rare condition and difficult to predict, it is prudent for health care providers to consider this disease, especially if the patient has signs and symptoms of renal failure at a young age with a family history of end-stage renal disease. However, even with limited knowledge, nephrologists can obtain the diagnosis and improve patient care with the help of the following criteria:</p><p>
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<b>Criteria for Suspecting a Diagnosis of ADTKD</b>
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</p><ul><li class="half_rhythm"><div>Family history is compatible with the autosomal dominant pattern of inheritance of CKD in line with clinical characteristics (as mentioned above).</div></li><li class="half_rhythm"><div>In the absence of a family history of CKD in line with clinical characteristics, demonstration of relevant histology on renal biopsy or extrarenal features compatible with HNF1B mutation, or history of early-onset hyperuricemia with or without gout.</div></li></ul><p>
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<b>Criteria for Establishing the Diagnosis of ADTKD</b>
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</p><ul><li class="half_rhythm"><div>Family history is compatible with the autosomal dominant pattern of inheritance of CKD in line with clinical characteristics (as mentioned above) and relevant histology in at least one affected relative. (Of note, it is not possible to establish a definitive diagnosis by kidney biopsy alone)or</div></li><li class="half_rhythm"><div>Demonstration of mutation in at least one of the four genes in the patient or at least one family member</div></li></ul><p>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.<a class="bk_pop" href="#article-24904.r6">[6]</a></p><p>In ADTKD-<i>MUC1, </i>genetic diagnosis is not straightforward. It is essential to know that testing for the <i>MUC1 </i>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 conducted to detect MUC1fs protein by immunostaining the MUC1fs protein on the epithelial tissues and the urinary cell smears in individuals with ADTKD-<i>MUC1,</i> and the result is promising. Still, it is not readily available at the clinical lab yet.<a class="bk_pop" href="#article-24904.r27">[27]</a></p><p>In ADTKD-<i>UMOD,</i> the diagnosis may be made based on the appropriate and relevant clinical scenario and the knowledge that another family member has been identified with a <i>UMOD</i> mutation on genetic testing. However, uromodulin genetic analysis is readily available at commercial clinical laboratories.<a class="bk_pop" href="#article-24904.r25">[25]</a></p><p>In ADTKD-<i>REN, </i>genetic analysis of the <i>REN</i> 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.<a class="bk_pop" href="#article-24904.r6">[6]</a></p><p>In ADTKD-<i>HNF1B, </i>this condition's clinical scenario is widely variable, with different renal and extrarenal clinical manifestations. The cost-effective NGS-based strategies allow rapid and simultaneous sequencing of several genes, including <i>HNF1B.</i><a class="bk_pop" href="#article-24904.r18">[18]</a></p><p>In ADTKD-<i>SEC61A1, </i>very few families have been diagnosed with this condition. Currently, the diagnostic criteria are still under development.</p></div><div id="article-24904.s9"><h2 id="_article-24904_s9_">Treatment / Management</h2><p>Treatment of autosomal dominant tubulointerstitial kidney disease mainly focuses on managing the symptoms associated with each type of disease and slowing down the progression to end-stage renal disease. It seems reasonable that potentially affected family members be well managed for other risk factors known to worsen or cause CKD, such as arterial hypertension, diabetes, smoking, and obesity, and annual kidney function testing is necessary. There are few treatment options for children at risk for UMOD- or MUC1-associated diseases. On the contrary, minors with HNF1B- and REN-associated diseases are likely to improve from early treatment. Affected individuals should typically be treated according to established CKD guidance.<a class="bk_pop" href="#article-24904.r28">[28]</a> The followings are the most important management options for each sub-type of the disease:</p><p>Regarding ADTKD-UMOD, allopurinol or febuxostat are the best treatment options for gout and hyperuricemia. Patients should be encouraged to take one of these medications as soon as gout develops to prevent further gout attacks and gouty tophi. Although starting allopurinol early in life may prevent gout from developing later, the risks and benefits should be discussed thoroughly with the patient or the family if the patient is minor because allopurinol has some important side effects and severe allergic reactions.<a class="bk_pop" href="#article-24904.r29">[29]</a> It is also essential to inform all women of child-bearing age that this medication may have some teratogenic effects and should be stopped before the pregnancy.<a class="bk_pop" href="#article-24904.r30">[30]</a> As kidney disease progression is typically slow, and the UMOD mutations affect only the kidneys, these patients are excellent renal transplantation candidates.</p><p>Regarding ADTKD-MUC1, there is no specific therapy at present. Optimal therapy to manage chronic kidney disease, such as controlling blood pressure and secondary chronic kidney disease changes, are the only available treatments for this condition. As progression to end-stage renal disease is at a slow rate, and the fact that this condition affects only the kidney, these patients are excellent candidates for renal transplantation.<a class="bk_pop" href="#article-24904.r6">[6]</a></p><p>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 for 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 hyperkalemia and hypotension and improve hyperuricemia but does not ameliorate hemoglobin levels. Fludrocortisone may slow chronic kidney disease progression by lowering renin production (both the normal and the mutated renin).<a class="bk_pop" href="#article-24904.r6">[6]</a></p><p>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. Renal ultrasound should be performed to evaluate renal morphologic abnormalities.<a class="bk_pop" href="#article-24904.r31">[31]</a><a class="bk_pop" href="#article-24904.r6">[6]</a></p><p>Regarding ADTKD-SEC61A1, there is no specific therapy to treat the underlying cause, but managing the associated congenital anemia and preventing opportunistic infection should be carried out for a better prognosis.</p><p>It is important to know that patients with ADTKD are excellent candidates for kidney transplantation, particularly if there are no extra-renal manifestations.<a class="bk_pop" href="#article-24904.r6">[6]</a></p></div><div id="article-24904.s10"><h2 id="_article-24904_s10_">Differential Diagnosis</h2><p>Autosomal dominant tubulointerstitial kidney disease is a congenital renal anomaly that ultimately leads to end-stage renal disease. This condition is inherited in an autosomal dominant manner. It is essential to exclude other congenital renal diseases before making the diagnosis.<a class="bk_pop" href="#article-24904.r24">[24]</a><a class="bk_pop" href="#article-24904.r25">[25]</a> The following consists of the most likely differential diagnosis of this condition:</p><ul><li class="half_rhythm"><div>Early-onset autosomal dominant polycystic kidney disease</div></li><li class="half_rhythm"><div>Autosomal recessive polycystic kidney disease</div></li><li class="half_rhythm"><div>Urinary tract obstruction</div></li><li class="half_rhythm"><div>Renal dysplasia</div></li><li class="half_rhythm"><div>Gout</div></li></ul></div><div id="article-24904.s11"><h2 id="_article-24904_s11_">Prognosis</h2><p>Although autosomal dominant tubulointerstitial kidney disease is considered benign, most cases will ultimately develop end-stage renal disease. To improve the prognosis, the treatment should focus on slowing the progression to ESRD. The mean age at which the ESRD develops 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 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.<a class="bk_pop" href="#article-24904.r6">[6]</a><a class="bk_pop" href="#article-24904.r29">[29]</a></p></div><div id="article-24904.s12"><h2 id="_article-24904_s12_">Complications</h2><p>ESRD is the most critical complication associated with autosomal dominant tubulointerstitial kidney disease. ESRD leads to variable health issues that should be addressed thoroughly and appropriately treated.<a class="bk_pop" href="#article-24904.r6">[6]</a><a class="bk_pop" href="#article-24904.r29">[29]</a> The followings encompass the most likely complications associated with ESRD:</p><ul><li class="half_rhythm"><div>Anemia </div></li><li class="half_rhythm"><div>Osteoporosis and fracture</div></li><li class="half_rhythm"><div>Platelet dysfunction with easy bruising</div></li><li class="half_rhythm"><div>Congestive heart failure</div></li><li class="half_rhythm"><div>Pericarditis</div></li><li class="half_rhythm"><div>Menstrual problems and infertility</div></li><li class="half_rhythm"><div>Hypertension</div></li><li class="half_rhythm"><div>Peripheral neuropathy</div></li><li class="half_rhythm"><div>Hyperkalemia and cardiac arrest</div></li></ul><p>In addition to the complications associated with ESRD, each form of this disease has certain complications that should be addressed as well to improve the patient quality of life as the following: </p><ul><li class="half_rhythm"><div>ADTKD-UMOD is associated with hyperuricemia and gout</div></li><li class="half_rhythm"><div>ADTKD-REN is associated with hypo-proliferative anemia, hyperuricemia, mild hypotension, mild hyperkalemia</div></li><li class="half_rhythm"><div>ADTKD-HNF1B is associated with maturity-onset diabetes of the young, abnormal liver function test of unclear etiology, genito-urinary tract malformations, hyperuricemia with gout, and hypomagnesemia</div></li><li class="half_rhythm"><div>ADTKD-SEC61A1 is associated with anemia and neutropenia with abscess formation</div></li></ul></div><div id="article-24904.s13"><h2 id="_article-24904_s13_">Consultations</h2><p>The management of autosomal dominant tubulointerstitial kidney disease and its complications require an interprofessional team consisting of the following:</p><ul><li class="half_rhythm"><div>Nephrologist</div></li><li class="half_rhythm"><div>Hepatologist</div></li><li class="half_rhythm"><div>Cardiologist</div></li><li class="half_rhythm"><div>Hematologist</div></li><li class="half_rhythm"><div>Nurse practitioners</div></li><li class="half_rhythm"><div>Pharmacists</div></li><li class="half_rhythm"><div>Hemodialysis technicians</div></li></ul></div><div id="article-24904.s14"><h2 id="_article-24904_s14_">Deterrence and Patient Education</h2><p>Patients with autosomal dominant tubulointerstitial kidney disease should be informed about this disease's congenital nature. Health professionals should clarify that there are no available medications to treat the underlying cause. The management plan should focus on preventive measures to slow the progression of the disease to ESRD and relieve the symptoms associated with each form of the disease.</p><p>Health care providers must also advise patients about the importance of medication adherence and compliance. Since this condition is transmitted in an autosomal dominant manner, other family members are likely to be affected even if they are asymptomatic, so screening for genetic mutations in the affected family members is rational.<a class="bk_pop" href="#article-24904.r6">[6]</a></p></div><div id="article-24904.s15"><h2 id="_article-24904_s15_">Enhancing Healthcare Team Outcomes </h2><p>The management of this condition requires the collaboration of the entire interprofessional team. The primary healthcare provider should be aware of this condition, especially if the patient presents with a progressive decline in renal function associated with bland urinary sediment. These patients should be referred to a nephrologist to manage renal insufficiency and prepare them for renal transplantation if mandatory. Nurses and pharmacists can also contribute with patient counseling about the condition, and in the case of pharmacists, regarding proper dosing and medication compliance. If it is confirmed that the patient carries the mutated gene, other family members should be screened for that mutation as their probability of being affected is high, and early screening could improve the prognosis and outcomes, so a genetics specialist may also need to be included in case management.</p><p>All interprofessional team members are responsible for documenting their observations and interventions in the patient's medical record, so all providers operate from the same data. If they notice any issues of concern, then open communication with appropriate team members is crucial to initiating proper therapeutic interventions so the patient will receive optimal care. This interprofessional model that includes clinicians, nurses, pharmacists, and other specialists will lead to the best patient outcomes. [Level 5]</p></div><div id="article-24904.s16"><h2 id="_article-24904_s16_">Review Questions</h2><ul><li class="half_rhythm"><div>
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Activation of the bumetanide-sensitive Na+,K+,2Cl- cotransporter (NKCC2) is facilitated by Tamm-Horsfall protein in a chloride-sensitive manner. <span><span class="ref-journal">J Biol Chem. </span>2011 Aug 26;<span class="ref-vol">286</span>(34):30200-10.</span> [<a href="/pmc/articles/PMC3191059/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3191059</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21737451" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21737451</span></a>]</div></dd><dt>15.</dt><dd><div class="bk_ref" id="article-24904.r15">Kidd K, Vylet'al P, Schaeffer C, Olinger E, Živná M, Hodaňová K, Robins V, Johnson E, Taylor A, Martin L, Izzi C, Jorge SC, Calado J, Torres RJ, Lhotta K, Steubl D, Gale DP, Gast C, Gombos E, Ainsworth HC, Chen YM, Almeida JR, de Souza CF, Silveira C, Raposeiro R, Weller N, Conlon PJ, Murray SL, Benson KA, Cavalleri GL, Votruba M, Vrbacká A, Amoroso A, Gianchino D, Caridi G, Ghiggeri GM, Divers J, Scolari F, Devuyst O, Rampoldi L, Kmoch S, Bleyer AJ. 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Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia. <span><span class="ref-journal">Am J Hum Genet. </span>2016 Jul 07;<span class="ref-vol">99</span>(1):174-87.</span> [<a href="/pmc/articles/PMC5005467/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5005467</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27392076" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27392076</span></a>]</div></dd><dt>17.</dt><dd><div class="bk_ref" id="article-24904.r17">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. <span><span class="ref-journal">Sci Rep. </span>2019 Aug 12;<span class="ref-vol">9</span>(1):11601.</span> [<a href="/pmc/articles/PMC6691008/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6691008</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31406136" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31406136</span></a>]</div></dd><dt>18.</dt><dd><div class="bk_ref" id="article-24904.r18">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. <span><span class="ref-journal">Kidney Int Rep. </span>2020 Dec;<span class="ref-vol">5</span>(12):2341-2350.</span> [<a href="/pmc/articles/PMC7710890/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7710890</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/33305128" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33305128</span></a>]</div></dd><dt>19.</dt><dd><div class="bk_ref" id="article-24904.r19">Bleyer AJ, Kmoch S, Antignac C, Robins V, Kidd K, Kelsoe JR, Hladik G, Klemmer P, Knohl SJ, Scheinman SJ, Vo N, Santi A, Harris A, Canaday O, Weller N, Hulick PJ, Vogel K, Rahbari-Oskoui FF, Tuazon J, Deltas C, Somers D, Megarbane A, Kimmel PL, Sperati CJ, Orr-Urtreger A, Ben-Shachar S, Waugh DA, McGinn S, Bleyer AJ, Hodanová K, Vylet'al P, Živná M, Hart TC, Hart PS. Variable clinical presentation of an MUC1 mutation causing medullary cystic kidney disease type 1. <span><span class="ref-journal">Clin J Am Soc Nephrol. </span>2014 Mar;<span class="ref-vol">9</span>(3):527-35.</span> [<a href="/pmc/articles/PMC3944763/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3944763</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24509297" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24509297</span></a>]</div></dd><dt>20.</dt><dd><div class="bk_ref" id="article-24904.r20">Ekici AB, Hackenbeck T, Morinière V, Pannes A, Buettner M, Uebe S, Janka R, Wiesener A, Hermann I, Grupp S, Hornberger M, Huber TB, Isbel N, Mangos G, McGinn S, Soreth-Rieke D, Beck BB, Uder M, Amann K, Antignac C, Reis A, Eckardt KU, Wiesener MS. Renal fibrosis is the common feature of autosomal dominant tubulointerstitial kidney diseases caused by mutations in mucin 1 or uromodulin. <span><span class="ref-journal">Kidney Int. </span>2014 Sep;<span class="ref-vol">86</span>(3):589-99.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24670410" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24670410</span></a>]</div></dd><dt>21.</dt><dd><div class="bk_ref" id="article-24904.r21">Nasr SH, Lucia JP, Galgano SJ, Markowitz GS, D'Agati VD. Uromodulin storage disease. <span><span class="ref-journal">Kidney Int. </span>2008 Apr;<span class="ref-vol">73</span>(8):971-6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18004297" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18004297</span></a>]</div></dd><dt>22.</dt><dd><div class="bk_ref" id="article-24904.r22">Hoefele J, Nayir A, Chaki M, Imm A, Allen SJ, Otto EA, Hildebrandt F. Pseudodominant inheritance of nephronophthisis caused by a homozygous NPHP1 deletion. <span><span class="ref-journal">Pediatr Nephrol. </span>2011 Jun;<span class="ref-vol">26</span>(6):967-71.</span> [<a href="/pmc/articles/PMC3342573/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3342573</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21258817" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21258817</span></a>]</div></dd><dt>23.</dt><dd><div class="bk_ref" id="article-24904.r23">Lens XM, Banet JF, Outeda P, Barrio-Lucía V. A novel pattern of mutation in uromodulin disorders: autosomal dominant medullary cystic kidney disease type 2, familial juvenile hyperuricemic nephropathy, and autosomal dominant glomerulocystic kidney disease. <span><span class="ref-journal">Am J Kidney Dis. </span>2005 Jul;<span class="ref-vol">46</span>(1):52-7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15983957" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15983957</span></a>]</div></dd><dt>24.</dt><dd><div class="bk_ref" id="article-24904.r24">Bleyer AJ, Živná M, Kidd K, Kmoch S. Autosomal Dominant Tubulointerstitial Kidney Disease – <em>MUC1</em>. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. <span class="ref-journal">GeneReviews<sup>®</sup> [Internet].</span> University of Washington, Seattle; Seattle (WA): Aug 15, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23946964" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23946964</span></a>]</div></dd><dt>25.</dt><dd><div class="bk_ref" id="article-24904.r25">Bleyer AJ, Kidd K, Živná M, Kmoch S. Autosomal Dominant Tubulointerstitial Kidney Disease – <em>UMOD</em>. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. <span class="ref-journal">GeneReviews<sup>®</sup> [Internet].</span> University of Washington, Seattle; Seattle (WA): Jan 12, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/20301530" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20301530</span></a>]</div></dd><dt>26.</dt><dd><div class="bk_ref" id="article-24904.r26">Verhave JC, Bech AP, Wetzels JF, Nijenhuis T. Hepatocyte Nuclear Factor 1β-Associated Kidney Disease: More than Renal Cysts and Diabetes. <span><span class="ref-journal">J Am Soc Nephrol. </span>2016 Feb;<span class="ref-vol">27</span>(2):345-53.</span> [<a href="/pmc/articles/PMC4731131/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4731131</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26319241" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26319241</span></a>]</div></dd><dt>27.</dt><dd><div class="bk_ref" id="article-24904.r27">Živná M, Kidd K, Přistoupilová A, Barešová V, DeFelice M, Blumenstiel B, Harden M, Conlon P, Lavin P, Connaughton DM, Hartmannová H, Hodaňová K, Stránecký V, Vrbacká A, Vyleťal P, Živný J, Votruba M, Sovová J, Hůlková H, Robins V, Perry R, Wenzel A, Beck BB, Seeman T, Viklický O, Rajnochová-Bloudíčková S, Papagregoriou G, Deltas CC, Alper SL, Greka A, Bleyer AJ, Kmoch S. Noninvasive Immunohistochemical Diagnosis and Novel <em>MUC1</em> Mutations Causing Autosomal Dominant Tubulointerstitial Kidney Disease. <span><span class="ref-journal">J Am Soc Nephrol. </span>2018 Sep;<span class="ref-vol">29</span>(9):2418-2431.</span> [<a href="/pmc/articles/PMC6115665/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6115665</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29967284" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29967284</span></a>]</div></dd><dt>28.</dt><dd><div class="bk_ref" id="article-24904.r28">Stevens PE, Levin A., Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members. 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<b>Disclosure: </b>Younus Shamam declares no relevant financial relationships with ineligible companies.</p></div></dd><dt></dt><dd><div><p class="no_top_margin">
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<b>Disclosure: </b>Muhammad Hashmi declares no relevant financial relationships with ineligible companies.</p></div></dd></dl></div></div></div>
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