INTRODUCTION — Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a group of uncommon genetic disorders characterized by progressive decline in kidney function and autosomal dominant inheritance [1]. There are approximately 500 families in the United States suffering from this condition, and the prevalence in other countries is likely to be similar. Individual families may have a large number of affected individuals due both to autosomal dominant inheritance and to the late onset of chronic kidney disease (CKD). Other families may have fewer affected individuals, with only a parent and child affected, or, rarely, even a single individual affected due to a de novo mutation. Underreporting due to incorrect diagnosis may contribute to the low estimated prevalence. ADTKD has generally included genetic disorders that primarily affect the kidney and have few non-kidney manifestations.

ADTKD should be suspected whenever a parent and a child both have CKD with absent or minimal proteinuria and a bland urinary sediment.

The etiology, clinical presentation, diagnosis, and treatment of the major subtypes of ADTKD are discussed in this topic. Discussions of other inherited renal disorders associated with progressive CKD, such as polycystic kidney disease, hereditary nephritis, and nephronophthisis, are presented elsewhere:

●(See "Autosomal dominant polycystic kidney disease (ADPKD) in adults: Epidemiology, clinical presentation, and diagnosis".)

●(See "Autosomal dominant polycystic kidney disease (ADPKD) in children".)

●(See "Autosomal recessive polycystic kidney disease in children".)

●(See "Clinical manifestations, diagnosis, and treatment of Alport syndrome (hereditary nephritis)".)

●(See "Clinical manifestations, diagnosis, and treatment of nephronophthisis".)

OVERVIEW AND CLASSIFICATION — ADTKD is characterized by the following features:

●Autosomal dominant inheritance.

●Slowly progressive kidney disease, with impaired kidney function typically appearing in the teenage years, and end-stage kidney disease (ESKD) onset that is highly variable, usually between the ages of 20 and 70 years.

●A bland urine sediment with no or minimal proteinuria.

●Kidney ultrasound reveals normal kidney size with increased echogenicity early in the disease course, with kidneys becoming smaller as chronic kidney disease (CKD) develops. Cysts develop at the same rate as in other chronic kidney diseases.

There are three known major genetic causes of ADTKD, all of which meet the above criteria, and each of which has distinguishing characteristics (table 1). These conditions have been given a number of names (eg, familial juvenile hyperuricemic nephropathy [FJHN], medullary cystic kidney disease). However, we agree with the Kidney Disease: Improving Global Outcomes (KDIGO) consensus report that provides standard terminology for these conditions [2]:

●ADTKD due to UMOD mutations (ADTKD-UMOD) – ADTKD-UMOD, also known as uromodulin kidney disease (UKD), is caused by mutations in the UMOD gene encoding uromodulin (also known as Tamm-Horsfall protein). In addition to progressive CKD, this disorder is characterized by gout occurring at an early age (sometimes even in the teenage years) in many, but not all, affected individuals [3].

ADTKD-UMOD is the most common subtype, accounting for approximately 70 percent of cases of ADTKD. In the past, it has been called medullary cystic kidney disease type 2 (MCKD2), FJHN, and uromodulin-associated kidney disease. (See 'ADTKD due to mutations in the UMOD gene (ADTKD-UMOD)' below.)

●ADTKD due to REN mutations (ADTKD-REN) – ADTKD-REN, which is due to mutations in the REN gene encoding renin, produces progressive CKD, low or low-normal blood pressures, anemia that occurs in childhood before the onset of CKD, mild hyperkalemia, and hyperuricemia [4]. This is a less common subtype of ADTKD, accounting for approximately 5 percent of families with ADTKD. In the past, it has been called familial juvenile hyperuricemic nephropathy type 2 (FJHN2). Fludrocortisone may be an effective therapy for this condition [5]. (See 'ADTKD due to mutations in the REN gene (ADTKD-REN)' below.)

●ADTKD due to MUC1 mutations (ADTKD-MUC1) – ADTKD-MUC1, also known as mucin-1 kidney disease (MKD), is caused by mutations in the MUC1 gene encoding mucin-1 and is associated with progressive CKD but no other distinguishing characteristics (ie, no precocious gout, childhood anemia, hypotension, or hyperkalemia). It accounts for approximately 30 percent of ADTKD [6]. In the past, this condition was called medullary cystic kidney disease type 1 (MCKD1). (See 'ADTKD due to mutations in the MUC1 gene (ADTKD-MUC1)' below.)

ADTKD DUE TO MUTATIONS IN THE UMOD GENE (ADTKD-UMOD) — ADTKD due to mutations in the UMOD gene (ADTKD-UMOD), also known as uromodulin kidney disease (UKD), is the most common subtype of ADTKD. ADTKD-UMOD has also been referred to as medullary cystic kidney disease type 2 (MCKD2) [3,7-10], familial juvenile hyperuricemic nephropathy (FJHN) [8,11-14], hereditary nephropathy associated with hyperuricemia and gout [15], uromodulin storage disease [16], and glomerulocystic kidney disease [8,17]. All of these terms have been used to describe families with mutations in the UMOD gene. A clinical distinction among these terms is not warranted [3]. We will use the term ADTKD-UMOD in the following discussion.

Genetics of ADTKD-UMOD — ADTKD-UMOD is due to mutations in the UMOD gene on chromosome 16p12, which encodes uromodulin (Tamm-Horsfall glycoprotein) [3,12,14]. The condition is autosomal dominant: One allele makes normal uromodulin, while the other allele makes the mutated uromodulin. Almost all patients have a mutation in exon 3, 4, or 5 [3,13], although some families have been reported with mutations in exons 6 [18], 7 [19], 8 [20], or 9 [21]. In addition, there are certain polymorphisms in the UMOD gene that, although not producing all of the clinical features of ADTKD-UMOD, may be associated with an increased risk of chronic kidney disease (CKD) in the general population [22,23]. A catalog of UMOD mutations is available online.

Pathogenesis of ADTKD-UMOD — Uromodulin is produced exclusively in the thick ascending limb of the loop of Henle [24]. It is an insoluble protein whose sticky, adherent properties are probably important in maintaining the water-tight integrity of the thick ascending limb [24,25]. Uromodulin also appears to facilitate intracellular trafficking of both the furosemide-sensitive Na-K-2Cl cotransporter [26] and the renal outer medullary potassium channel (ROMK) [27] to the apical surface of the thick ascending limb tubular cells (figure 1).

More than one-half of the mutations identified in the UMOD gene are missense mutations resulting in the deletion or addition of a cysteine residue [19]. These mutant uromodulin proteins are unable to assemble properly and cannot exit the endoplasmic reticulum [9,28,29], resulting in accumulation of uromodulin within the cells of the thick ascending limb of the loop of Henle. These changes have been found to lead to mitochondrial dysregulation and a decreased number of mitochondria in thick ascending limb cells [30].

Intracellular accumulation of abnormal uromodulin proteins can lead to tubular cell atrophy and death [12,28]. In addition, the abnormal uromodulin appears to impair the synthesis and secretion of normal uromodulin produced from the unaffected allele, resulting in a marked reduction in urinary uromodulin excretion [12,31].

The two major pathophysiologic effects of UMOD mutations are hyperuricemia and progressive CKD:

●Hyperuricemia results from reduced urate excretion [12,32,33]. Uromodulin facilitates the intracellular trafficking of the furosemide-sensitive Na-K-2Cl transporter to the apical membrane of the thick ascending limb [34]. Due to decreased uromodulin production, there is decreased apical expression of the Na-K-2Cl cotransporter, resulting in a mild natriuresis. This defect is postulated to result in mild sodium wasting and volume contraction. Compensatory proximal tubular sodium reabsorption then occurs, which restores volume status to normal. However, this results in a secondary increase in proximal urate reabsorption as urate reabsorption follows sodium reabsorption [12,32]. Clinically, this manifests as a reduced fractional excretion of uric acid (FEUA) and hyperuricemia.

●Progressive CKD may be related to tubular cell death in the thick ascending limb due to intracellular accumulation of mutant uromodulin [29,35]. Kidney biopsies reveal tubulointerstitial disease. The possible therapeutic role for allopurinol in slowing kidney disease progression is discussed below. (See 'Treatment of ADTKD-UMOD' below.)

In addition to its effects on water impermeability and ion transport in the thick ascending limb, rodent data suggest that uromodulin protects against urinary tract infection [25,36] and inhibits formation of renal calculi. However, patients with ADTKD-UMOD do not have an increased incidence of urinary tract infection [32] or kidney stones [11,32].

Clinical presentation of ADTKD-UMOD — De novo mutations resulting in ADTKD-UMOD are rare. Thus, most affected individuals present in the setting of a family with a strong history of gout and inherited kidney disease. Previously, many of these families were undiagnosed and uncertain of the cause of inherited kidney disease. Increasingly, families are aware of the ADTKD-UMOD diagnosis. The most common clinical presentations of ADTKD-UMOD are as follows:

●Precocious gout – Affected individuals may develop gout in their teenage years; the median age of onset is approximately 25 years [37]. Gout in this condition is caused by hyperuricemia resulting from a reduced FEUA. As there is usually a strong family history of gout and kidney disease, parents are quick to identify the gout and usually refer their child for further testing. (See 'Gout' below.)

●CKD – Patients with ADTKD-UMOD can present with an incidentally discovered elevated serum creatinine and/or progressive CKD, a bland urine (ie, no proteinuria or hematuria), and a kidney ultrasound that is typically normal (although kidneys may be small if CKD is advanced). If performed, a kidney biopsy reveals nonspecific tubulointerstitial fibrosis. The age of onset of CKD in such patients is highly variable. (See 'Chronic kidney disease' below.)

●Family history of gout and CKD – Increasingly, families will have knowledge of the ADTKD-UMOD diagnosis, and younger family members will ask for genetic screening to see whether ADTKD-UMOD is present.

Often, presenting patients will have all three manifestations (gout, an elevated serum creatinine, and a positive family history).

Gout — In the general population, gout usually occurs in middle-aged men in the setting of obesity or CKD. However, gout in ADTKD-UMOD often has an earlier age of onset, sometimes in the teenage years. Women with ADTKD-UMOD are also frequently affected by gout. As an example, in a series of 205 patients from 31 affected families with ADTKD-UMOD, 65 percent had gout, although this feature was absent in some families [16].

Asymptomatic hyperuricemia is even more frequent. It can often be detected during childhood if testing is performed early because of a positive family history. In the series mentioned above, 75 percent of patients had hyperuricemia.

Hyperuricemia in patients with ADTKD-UMOD is caused by a low FEUA (ie, they are underexcretors) [13,15,32,38]. The FEUA can be calculated from a random urine specimen using the same formula that is used to calculate the fractional excretion of sodium, substituting uric acid for sodium using either standard units (calculator 1) or the International System of Units (SI) units (calculator 2):

Underexcretion is defined as an FEUA less than 6 percent and is often below 4 percent [32]. Normal values in healthy adults are 8±3 percent in males and 13±3 percent in females [39]. The normal FEUA in healthy children is even higher (18±5 percent) [39,40].

An important caveat is that the FEUA and other solutes, such as sodium, increases as kidney function worsens (ie, as the filtered load falls). The expected values for FEUA cited above only apply to patients with an estimated glomerular filtration rate above 70 mL/min per 1.73 m² [32,40,41]. Higher values would be seen at lower filtration rates. This issue is discussed in detail elsewhere. (See "Fractional excretion of sodium, urea, and other molecules in acute kidney injury".)

Chronic kidney disease — Patients with ADTKD-UMOD develop slowly progressive CKD, with a median age of end-stage kidney disease (ESKD) of 54 years [37]. Affected individuals often present with a mild elevation in serum creatinine, sometimes during the teenage years [9]. Kidney disease progression is highly variable between and within families. Some individuals may develop ESKD in their 20s, while others may not require kidney replacement therapy until past 70 years of age. Kidney disease is milder in women than in men [42].

In the review of 205 patients mentioned above, 70 percent had CKD [16]. The CKD progressed in 80 percent of these patients, with ESKD developing between the ages of 20 and 70 years. Similar observations were made in a series of 109 patients from 45 families [20]; the median age at ESKD onset was 54 years (range was 25 to 70 years). Some patients are mildly affected, with estimated glomerular filtration rate values >50 mL/min per 1.73 m² even after the age of 70 years.

The urinalysis in patients with ADTKD-UMOD reveals little, if any, protein and no blood. This is a consistent finding among affected family members and helps to distinguish this disorder (and other subtypes of ADTKD) from more common inherited kidney diseases that often affect the glomerulus (eg, thin basement membrane nephropathy).

Occasionally, patients with ADTKD-UMOD will have microscopic hematuria; however, this finding is not a manifestation of the disorder but is instead a coincidental finding, because microscopic hematuria is not uncommon in the general population. If many family members suffer from hematuria, the family may be tested for UMOD mutations, but other etiologies should be strongly suspected.

Diagnosis of ADTKD-UMOD — A presumptive diagnosis of ADTKD-UMOD can be made based upon clinical manifestations (early-onset gout, unexplained CKD with a bland urine) and a strong family history of gout or CKD. The diagnosis is confirmed through genetic testing.

Although a kidney biopsy is sometimes performed in patients with unexplained CKD, it is not diagnostic of ADTKD-UMOD. As a result (and because genetic testing can confirm the diagnosis in patients presumed to have ADTKD), we do not perform a kidney biopsy as part of the routine diagnostic work-up of patients with suspected ADTKD-UMOD.

However, kidney biopsy is occasionally performed to evaluate CKD in affected patients when ADTKD-UMOD has not been considered. In these patients, the typical finding is diffuse tubulointerstitial fibrosis [9,15,29]. Tubular dilatations, which can enlarge to tubular cysts, may be present, but uric acid crystals are not seen [15]. Glomerulocystic changes have been identified in two families [8,17], but they are not typical.

These pathologic changes are not pathognomonic, and pathologists will rarely make the diagnosis based solely upon the biopsy results. Immunofluorescence microscopy with antibodies to uromodulin can be performed, which will demonstrate abnormal deposition of uromodulin in tubular cells [9]. This immunohistochemical staining is not available in most pathology laboratories and is not routinely performed.

Presumptive clinical diagnosis — A presumptive clinical diagnosis of ADTKD-UMOD in an individual presenting with gout and/or CKD relies upon three factors:

●A strong family history of kidney disease in a pattern suggestive of autosomal dominant inheritance

●A family history of gout

●A bland urinary sediment with little or no proteinuria

One or both of the first two factors may be missing in patients with spontaneous mutations (which are rare) or if the family history is incomplete. It is important to include information about all family members, including aunts, uncles, and grandparents, and to obtain medical records from as many family members as possible. The identification of the disease may be missed if the parent is mildly affected (especially the mother), the parent has died from another condition prior to the development of kidney failure, or if the status of the affected parent is unknown.

Confirm with genetic testing of the UMOD gene — Mutational analysis of the UMOD gene can be obtained to make a definitive diagnosis of ADTKD-UMOD. The test is available commercially from a number of laboratories, which can be viewed here. If the mutation causing ADTKD-UMOD is already known in the family, genetic testing can be performed specifically for this mutation. Such testing is less expensive and preferred. If the mutation in the family is unknown, genetic testing should be performed at a laboratory that examines all exons of the gene (ie, not just the exons where mutations most commonly occur). Some of these laboratories analyze only exons 4 and 5 of the UMOD gene, sites at which almost all mutations occur. If these laboratories are used, mutations occurring in other exons (although uncommon) will be missed [19]. (See 'Genetics of ADTKD-UMOD' above.)

Genetic testing can be expensive. Thus, it may be preferable to test a family member who is definitely affected (based upon clinical features) and who has sufficient financial resources or insurance for the test. Once a genetic diagnosis has been made in the family, genetic testing for the specific mutation (which is less expensive) can then be made in other potentially affected members on a case-by-case basis. For some individuals, clinical findings, together with a family history of a reported mutation, suffice for diagnosis. As examples:

●Individuals with CKD, hyperuricemia, and a bland sediment may not need to be tested if a UMOD mutation has already been identified in other affected members of the family, as there is no specific therapy. (See 'Treatment of ADTKD-UMOD' below.)

●Individuals from affected families who have normal kidney function and normal serum uric acid levels are much less likely to have ADTKD-UMOD and present a diagnostic challenge. On the one hand, some of these individuals may have ADTKD-UMOD, and a certain diagnosis cannot be made without testing. On the other hand, positive genetic testing will deliver a diagnosis that may preclude obtaining life insurance and possibly health insurance in the future. We therefore recommend a detailed discussion with the patient. Genetic counseling may be helpful. If the patient is considering kidney donation, genetic testing is required.

A nephrologist often sees patients with unexplained CKD and hyperuricemia who do not have a family history of inherited kidney disease. These patients could suffer from ADTKD-UMOD, but the development of a de novo mutation in the UMOD gene is rare. As there is no specific therapy for this disorder, we do not recommend screening all individuals with unexplained CKD and hyperuricemia for UMOD mutations. Given that a number of genetic conditions can present with a bland urinary sediment and CKD, one may consider a kidney disease gene panel if genetic screening is considered.

Differential diagnosis of ADTKD-UMOD — The differential diagnosis of ADTKD-UMOD depends upon the clinical setting:

●In patients with a family history of unexplained CKD, the urinalysis is helpful in distinguishing ADTKD-UMOD from other forms of inherited kidney disease. The absence of hematuria or significant proteinuria helps to exclude genetic glomerular diseases, such as Alport syndrome (usually X-linked with frequent hematuria and proteinuria) or congenital focal segmental glomerulosclerosis (in which nephrotic syndrome is present). (See "Genetics, pathogenesis, and pathology of Alport syndrome (hereditary nephritis)" and "Focal segmental glomerulosclerosis: Genetic causes".)

●In young individuals presenting with gout, the differential diagnosis includes other potential causes of early-onset hyperuricemia, such as hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency (Lesch-Nyhan) syndrome, kidney disease known to be caused by a different disorder, or the use of thiazide diuretics. These diagnoses are usually obvious from the clinical evaluation. A strong family history of gout and CKD would suggest a UMOD or REN mutation. Urinary examination in ADTKD reveals a low FEUA. If the 24-hour urine collection (while the patient is off of allopurinol or febuxostat) reveals 700 mg/day of uric acid in women and >800 mg/day in men, uric acid overproduction syndromes such as HPRT deficiency should be considered. (See "Diuretic-induced hyperuricemia and gout" and 'ADTKD due to mutations in the REN gene (ADTKD-REN)' below and "Overweight and obesity in adults: Health consequences", section on 'Gout'.)

●If a patient presents with medullary cysts by an imaging study, the differential diagnosis includes other kidney diseases affecting the medulla of the kidney, such as Dent disease or nephronophthisis. Acquired cystic diseases, often associated with CKD, can be distinguished from ADTKD because a family history of CKD and gout will usually be absent:

•(See "Renal cystic diseases in children".)

•(See "Dent disease (X-linked recessive nephrolithiasis)".)

•(See "Clinical manifestations, diagnosis, and treatment of nephronophthisis".)

•(See "Medullary sponge kidney".)

•(See "Acquired cystic disease of the kidney in adults".)

Treatment of ADTKD-UMOD — There is no specific therapy available for ADTKD-UMOD. Treatment includes management of gout as well as management of progressive CKD.

Treatment of gout — Patients with ADTKD-UMOD who develop gout should be treated with a xanthine oxidase inhibitor. Allopurinol has been studied in this disorder and should be the first choice [3]; febuxostat is an alternative agent. Studies have shown an increased risk of cardiovascular events with febuxostat versus allopurinol. In patients with gout who cannot tolerate allopurinol or are known to be at high risk of adverse reactions to allopurinol, the risks of progressive, tophaceous, lifelong gout must be balanced against the potential cardiovascular risks of febuxostat. As gout from ADTKD-UMOD is due to a reduced renal excretion of urate, conventional doses of allopurinol or febuxostat should be able to control gout in this disorder. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Xanthine oxidase inhibitors'.)

A separate issue is whether allopurinol or febuxostat might slow the rate of progression of the CKD in ADTKD-UMOD. This is discussed below. (See 'Treatment of CKD' below.)

Treatment of CKD

Prevention of CKD progression — As mentioned above, the hyperuricemia in ADTKD-UMOD results from relative underexcretion, not overproduction as in acute urate nephropathy. In addition, uric acid crystals have not been identified when kidney biopsy is performed [15]. Thus, it is not known whether uric acid plays a role in the pathogenesis of chronic kidney disease (CKD) in such patients.

Several observational studies have examined the association between uric acid-lowering drugs and progression of CKD in ADTKD-UMOD [15,32,43-45]. The best data come from a report of 27 patients with FJHN (now called ADTKD-UMOD), in which the diagnosis was made on clinical grounds before the advent of UMOD gene testing [43]. All were treated with allopurinol before the onset of gout, and the efficacy of therapy appeared to depend upon when the drug was initiated. Progression to ESKD within 2 to 10 years occurred in five of six patients in whom allopurinol was initiated when the serum creatinine was greater than 2.3 mg/dL (200 micromol/L). By contrast, no patient who started allopurinol therapy when the serum creatinine was less than 2.3 mg/dL (200 micromol/L) progressed to ESKD during 10 to 34 years of follow-up. In eight of these patients without CKD at the time they initiated allopurinol, kidney function remained unchanged for up to 20 years.

Although these data suggesting a benefit of allopurinol on CKD progression are weak, individuals with ADTKD-UMOD are also at significant risk of future gout, and allopurinol will prevent such attacks. In practice, our approach in patients who have not yet developed gout is to discuss the known benefit of future gout prevention, the possible benefit of slowing CKD progression, and the small risk of severe allergic reaction (see "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Xanthine oxidase inhibitors'). We also discuss that the medication is given indefinitely. As most patients have a strong family history of ADTKD-UMOD, they are usually familiar with both gout and the use of allopurinol.

Allopurinol and febuxostat should not be given to pregnant women or women who are at risk of becoming pregnant.

Management of CKD manifestations — Most patients with ADTKD-UMOD are normotensive and do not have substantial proteinuria. As a result, they are less likely to be treated with angiotensin inhibitors, which can slow the progression of proteinuric chronic kidney disease (CKD). There is no evidence that angiotensin inhibitors slow the progression of CKD in patients with ADTKD-UMOD. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

Due to a mild natriuresis, hypertension is uncommon in ADTKD-UMOD. In patients who are hypertensive, losartan would be a preferable treatment as it has been shown to increase urinary uric acid excretion. By contrast, diuretics will increase urate absorption and therefore are not preferred for the treatment of hypertension. (See "Diuretic-induced hyperuricemia and gout", section on 'Benefits of angiotensin inhibition and losartan'.)

The management of other manifestations of CKD, such as anemia and hyperphosphatemia, and the treatment of ESKD are similar to that in patients without ADTKD-UMOD. (See "Overview of the management of chronic kidney disease in adults".)

Patients with ADTKD-UMOD are excellent candidates for kidney transplantation since the disease does not recur in the transplanted kidney, and there are no other systemic manifestations except gout. Preemptive kidney transplantation should be the goal, and discussions regarding potential transplantation should begin when estimated glomerular filtration rate (eGFR) falls below 30 mL/min per 1.73 m². Patients should be referred for transplant evaluation as soon as the eGFR falls below 20 mL/min per 1.73 m² and be placed on the waiting list (in the United States) if they have no potential living donors. CKD progression remains slow, and patients may accrue three to four years of waiting time prior to the need for kidney replacement therapy. Family members should undergo genetic testing prior to donating a kidney, even if they appear to have normal kidney function. (See 'Confirm with genetic testing of the UMOD gene' above.)

The author is interested in discussing potential and established cases of ADTKD-UMOD with the reader. Author e-mail: [email protected].

ADTKD DUE TO MUTATIONS IN THE REN GENE (ADTKD-REN) — REN gene mutations are the least common cause of ADTKD, but they are also the most distinctive. It is the only ADTKD subtype for which a specific treatment is available; the clinical manifestations resemble those found in other low-renin states. (See 'Clinical presentation of ADTKD-REN' below.)

ADTKD due to REN mutations (ADTKD-REN) has also been referred to as familial juvenile hyperuricemic nephropathy type 2 (FJHN2).

Genetics of ADTKD-REN — ADTKD-REN is caused by mutations in the REN gene on chromosome 1 that encodes renin [4,5,46]. Mutations may occur in segments of the gene encoding the promoter, prosegment, or mature renin peptide [47].

ADTKD-REN, like other types of ADTKD, is autosomal dominant; clinically affected individuals have one normal gene and one abnormal gene. The parent of an affected individual is affected, and there is a 50 percent chance that the children of an affected individual will have the condition.

Pathogenesis of ADTKD-REN — Renin is expressed in multiple segments of the renal tubule, including the juxtaglomerular complex. In these cells, preprorenin is translocated into the endoplasmic reticulum, where it is converted to prorenin [48]. Some prorenin is secreted, while the remainder is targeted to lysozymes, where it is further cleaved to active renin. Mutations may occur in the segment of the gene encoding the promoter, prosegment, or mature renin peptide [4,5,47]. REN signal peptide mutations prevent translocation across the endoplasmic reticulum. REN prosegment mutations prevent proper folding of prorenin, and REN mutations in the mature renin peptide cause deposition of the mutated renin in the endoplasmic reticulum.

As the condition is autosomal dominant, a mutation occurs in one allele, while the other allele functions normally. Loss of production of normal renin by the mutated allele results in decreased production of renin. In addition, the cells producing renin are damaged due to intracellular accumulation of the mutated protein, further decreasing production of the hormone. Plasma renin levels in affected patients are low, although they may rise into the low-normal range during periods of stress. The low-renin state produces characteristic clinical findings. (See 'Clinical presentation of ADTKD-REN' below.)

Accumulation of preprorenin in renal tubular cells leads to ultrastructural damage and apoptosis of renal tubular cells [4,5]. As a result, affected individuals develop chronic kidney disease (CKD).

Clinical presentation of ADTKD-REN — The clinical features of ADTKD-REN were best characterized in an international, multicenter study of 111 individuals from 30 families with REN mutations [47]. In general, patients with mutations in the promoter or prosegment of the REN gene present early in life, while those with mutations in the mature renin peptide present in their 20s with gout and develop CKD later in life, similar to patients with ADTKD-UMOD.

Patients with ADTKD-REN due to mutations in the REN promoter or prosegment present with the following characteristics [5]:

●Clinical findings associated with a low-renin state, including:

•Low-normal blood pressure – A deficient renin-angiotensin system usually results in low-normal blood pressure. Some of the patients may be symptomatic with low blood pressure.

•Mild elevation in serum potassium – The renin-angiotensin system is involved in potassium handling by the kidney, and a low-renin state can impair potassium secretion, resulting in elevation of the serum potassium.

Acidosis may also be present early in life, requiring alkali supplementation.

•A propensity to prerenal azotemia – Similar to patients taking an angiotensin-converting enzyme (ACE) inhibitor, affected patients may be at increased risk for acute kidney injury in the setting of volume depletion and/or when nonsteroidal antiinflammatory drugs are used. In several instances, children have presented with acute kidney injury in the setting of a febrile illness, nausea, and the use of nonsteroidal antiinflammatory drugs. The acute kidney injury resolves quickly, but baseline CKD and anemia persist.

•Hypoproliferative anemia – Anemia, with low erythropoietin levels (ie, hypoproliferative), has been noted as early as one year of life and has been found to occur in all individuals with REN mutations. The anemia is associated with low erythropoietin levels, a low reticulocyte count, and normal levels of iron, folate, and B12. Hemoglobin levels range from 8 to 11 g/dL. The anemia responds to treatment with erythropoietin.

The anemia precedes the development of CKD and is thought to result from decreased levels of angiotensin, as has been noted in some patients taking angiotensin inhibitors. The anemia resolves with adolescence, implying that sex hormones may compensate for the effect of low angiotensin levels on erythrocyte production. The anemia recurs as CKD progresses. (See "Kidney transplantation in adults: Posttransplant erythrocytosis", section on 'ACE inhibitors or ARBs in all patients'.)

●CKD – Patients often present with decreased estimated glomerular filtration rate (eGFR) early in life, often with an eGFR <60 mL/min per 1.73 m². Despite this, progression is very slow, with children rarely requiring dialysis before age 18 years and a mean age of end-stage kidney disease (ESKD) of 52 years. As with other forms of ADTKD, the urinalysis is usually bland, without hematuria or significant proteinuria. The kidney ultrasound is normal early in the course of disease, but kidneys decrease in size as CKD progresses; medullary cysts may be present but are neither sensitive nor specific for this condition.

●Polyuria is seen in some, but not all, individuals with this disorder.

●Hyperuricemia is present from childhood, and gout may be seen in the early adult years. The mechanism underlying hyperuricemia is unclear, but it may result from relative hypotension and a consequent increase in proximal tubule sodium reabsorption with an associated increase in proximal urate reabsorption.

●A family history of CKD is present, with an autosomal dominant pattern of inheritance. Many members of the family suffer from CKD, and a parent of an affected patient almost always has CKD.

Patients with mutations in the mature REN peptide present between 20 and 30 years of age with gout as their first symptom. They do not suffer from anemia or hyperkalemia. They develop slowly progressive CKD and proceed to ESKD at a mean age of 64 years.

Diagnosis of ADTKD-REN — A presumptive diagnosis of ADTKD-REN can be made based upon clinical manifestations and a strong family history of CKD. The diagnosis is confirmed through genetic testing. (See 'Clinical presentation of ADTKD-REN' above and 'Confirm with genetic testing of the REN gene' below.)

ADTKD-REN should be strongly considered in a child who presents with one of the following in combination with a family history of CKD:

●Unexplained anemia that, if the serum creatinine is elevated, is out of proportion to the reduction in estimated glomerular filtration rate

●Acute kidney injury

●CKD in conjunction with hyperkalemia, low or low-normal blood pressure, and hyperuricemia

Neither renin levels nor a kidney biopsy are helpful in making a diagnosis of ADTKD-REN. Renin levels are usually in the low-normal range when they are obtained in a clinical setting that can increase renin levels (eg, under periods of stress). Findings on kidney biopsy are not specific, and, therefore, we do not perform a biopsy to diagnose this disorder. If performed, the biopsy reveals tubulointerstitial fibrosis.

Mutations in the mature renin peptide should be considered in individuals who have a clinical phenotype identical to those with ADTKD-UMOD but in whom UMOD genetic sequencing is negative. (See 'Clinical presentation of ADTKD-UMOD' above.)

Confirm with genetic testing of the REN gene — Mutational analysis of the REN gene can be obtained to make a definitive diagnosis of ADTKD-REN. Several laboratories can perform this analysis; information can be found here.

Differential diagnosis of ADTKD-REN — As with other types of ADTKD, examination of the urine can help to distinguish ADTKD-REN from other childhood causes of CKD, both genetic and acquired, which often affect the glomerulus (such as congenital focal segmental glomerulosclerosis, Alport syndrome, poststreptococcal glomerulonephritis, and immunoglobulin A [IgA] nephropathy). These disorders feature blood and/or protein in the urine, whereas patients with REN mutations have a bland urinary sediment.

●(See "Genetics, pathogenesis, and pathology of Alport syndrome (hereditary nephritis)".)

●(See "Focal segmental glomerulosclerosis: Genetic causes".)

●(See "Poststreptococcal glomerulonephritis".)

●(See "IgA nephropathy: Clinical features and diagnosis".)

The presence of anemia in childhood, the propensity to acute kidney injury, and the presence of mild hyperkalemia are clinical features that can differentiate ADTKD-REN from other subtypes of ADTKD (ie, ADTKD-UMOD or ADTKD-MUC1). (See 'Clinical presentation of ADTKD-REN' above.)

In addition to ADTKD-REN, the combination of progressive CKD and unexplained anemia in children can result from nephronophthisis, which is a group of autosomal recessive disorders involving mutations in proteins in the renal cilia. However, these conditions can be differentiated from disease due to REN mutations based upon the following:

●Inheritance pattern – A parent of the child with a REN mutation will have CKD and will have suffered from anemia as a child, prior to the onset of CKD; by contrast, neither parent of a child with nephronophthisis (which is autosomal recessive) will have CKD, and hemoglobin levels will be consistent with the level of kidney function.

●Severity of CKD – Patients with nephronophthisis have more advanced kidney failure than patients with REN mutations, and they usually develop ESKD in their teens or early 20s.

Treatment of ADTKD-REN — Treatment of anemia depends upon whether or not the patient is symptomatic. Some affected individuals do well with a hemoglobin between 10 and 11 g/dL and do not require therapy [47]. Other patients who are symptomatic and/or have lower hemoglobin levels should be treated with erythropoietin.

Patients tend to have low-normal blood pressures and mild hyperkalemia. Some of the patients may be symptomatic with the low blood pressure readings. Low blood pressure and hyperkalemia respond well to treatment with fludrocortisone. The increase in blood pressure also results in hemodynamic improvements and, consequently, an increase in the glomerular filtration rate and a lowering of the serum creatinine. A high-sodium diet can be employed as an alternative to fludrocortisone therapy.

Fludrocortisone and a high-sodium diet may also preserve kidney function, although this is hypothetical. Patients with this disorder develop CKD due to intracellular deposition of abnormal renin and subsequent tubular cell death. Thus, eliminating stimuli to renin production (eg, by using a mineralocorticoid receptor agonist and a high-sodium diet) could theoretically suppress synthesis of preprorenin and therefore diminish the accumulation of abnormal renin in cells. (See 'Pathogenesis of ADTKD-REN' above.)

Because patients with ADTKD-REN have a low-renin state with reduced activity of the renin-angiotensin system (similar to a patient receiving ACE inhibitors), it is important to avoid the use of nonsteroidal antiinflammatory drugs and to avoid placing these patients on a low-sodium diet. Children with this disorder are often seen by nephrologists, nurses, and dietitians who are in the habit of prescribing a low-sodium diet to patients with CKD. However, a low-sodium diet can cause hypotension and hyperkalemia and can predispose to acute kidney injury.

Kidney transplantation is effective in this disorder, with resolution of the clinical manifestations, even though renin is produced in other areas of the body besides the kidney. (See "Overview of the renin-angiotensin system".)

The author is interested in discussing potential and established cases of ADTKD-REN with the reader. Author e-mail: [email protected].

ADTKD DUE TO MUTATIONS IN THE MUC1 GENE (ADTKD-MUC1) — Mutations in the MUC1 gene encoding mucin-1 cause a subtype of ADTKD previously referred to as medullary cystic kidney disease type 1 (MCKD1) or mucin-1 kidney disease (MKD) and now referred to as ADTKD-MUC1 (table 1) [6].

Genetics of ADTKD-MUC1 — The MUC1 gene is located on chromosome 1q21 [49-54]. Most affected families suffer from a single cytosine insertion into one variable-number tandem repeat sequence within the MUC1 coding region that leads to the creation of a specific frameshift protein [6]. New mutations have been identified that also cause ADTKD-MUC1, all of which result in the creation of the same frameshift protein that is created by the cytosine insertion [55]. This mutation results in an abnormal mucin-1 protein that localizes intracellularly in the loop of Henle, distal tubule, and collecting duct.

Pathogenesis of ADTKD-MUC1 — The pathophysiology of the renal findings in patients with ADTKD-MUC1 is not understood. However, knockout studies in mice indicate that mucin-1 may not be an essential protein; therefore, it is possible that the MUC1 mutation in affected patients has a dominant negative or gain-of-function effect [6]. Mucin-1 is produced in the breast, skin, gastrointestinal tract, and respiratory system. It is unclear why the clinical phenotype resulting from MUC1 mutation is manifested only in the kidney [56].

Clinical presentation of ADTKD-MUC1

Autosomal dominant CKD — The primary manifestation of the MUC1 mutation is progressive chronic kidney disease (CKD) that follows an autosomal dominant pattern of inheritance. Many members of the family suffer from kidney disease, with a parent of an affected individual almost always having kidney disease and approximately 50 percent of children of an affected individual having CKD.

Some patients develop hyperuricemia and gout; however, unlike ADTKD due to UMOD mutations (ADTKD-UMOD) and ADTKD due to REN mutations (ADTKD-REN), gout is a late manifestation, and the hyperuricemia is proportional to the degree of kidney dysfunction.

As a result, most patients with MUC1 mutations present in one of two ways:

●Patients present with an unexplained elevated serum creatinine level during laboratory testing performed for other reasons, or they have unexplained progressive CKD. The urinalysis is relatively bland, without hematuria or significant proteinuria [52]. A kidney ultrasound typically reveals normal kidneys, although the kidneys may be small in size if the CKD is advanced. The kidney ultrasound may or may not detect medullary cysts, which are neither sensitive nor specific for this disorder. Patients presenting in this way frequently have family members with kidney disease of unknown etiology.

●They are members of a family in which many individuals are already known to have inherited CKD, and they come forward for screening to determine whether or not they are affected. Increasingly, family members are aware of a diagnosis of ADTKD-MUC1 in their families and present for screening while asymptomatic.

The course of CKD in affected families can be highly variable [52]. In a study of 72 patients from six Cypriot families, for example, some had CKD noted during the teenage years with development of end-stage kidney disease (ESKD) before age 30 years, while other patients had only moderate kidney dysfunction into their 60s. Similar variability was noted in a study of five families from Finland [50]. In one family, symptoms began before age 30 years, and ESKD or death occurred between the ages of 25 and 33 years. In another family, ESKD or death occurred between the ages of 34 and 55 years. One carrier died at age 64 years with no symptoms or signs of kidney disease.

As mentioned above, hyperuricemia and gout are not early findings, which helps to distinguish this disease from ADTKD-UMOD and ADTKD-REN. However, as kidney function declines, the risk of gout increases, but the increased risk is not out of proportion to the degree of kidney dysfunction. As an example, in the study of 72 affected individuals from six Cypriot families [52], hyperuricemia (defined as a serum uric acid above 7.0 mg/dL [416 micromol/L] in males and 6.0 mg/dL [357 micromol/L] in females) was present in 12 percent of patients with a creatinine clearance of 80 mL/min per 1.73 m² or higher, 45 percent in patients with a creatinine clearance 11 to 79 mL/min per 1.73 m², and 81 percent in patients with a creatinine clearance less than 11 mL/min per 1.73 m².

The prevalence of hypertension is also related to kidney function. In the same Cypriot patients, the prevalence of hypertension was 18, 48, and 77 percent with a creatinine clearance of 80 mL/min per 1.73 m² or higher, 11 to 79 mL/min per 1.73 m², and less than 11 mL/min per 1.73 m², respectively [52].

Other manifestations associated with progressive CKD (eg, anemia, renal osteodystrophy) occur at approximately the same rate as in other causes of CKD. (See "Overview of the management of chronic kidney disease in adults".)

Medullary cysts — Medullary cysts are uncommon but may be apparent on various imaging studies, such as computed tomography, intravenous pyelography, ultrasound, or magnetic resonance imaging enhanced by gadolinium [57,58].

Renal cysts are common but are not diagnostic in patients with ADTKD-MUC1. In the review of 72 Cypriot carriers, ultrasonography demonstrated cysts in 40 percent of tested carriers compared with 17 percent of normal controls [52]. The cysts were bilateral in approximately 60 percent of cases. Most cysts were corticomedullary or medullary, but cortical cysts were also seen.

Diagnosis of ADTKD-MUC1 — The diagnosis of ADTKD-MUC1 is suspected based upon clinical manifestations and the family history, and it can be confirmed through genetic testing.

Kidney biopsy is not part of the diagnostic evaluation of ADTKD-MUC1. If a kidney biopsy is performed in such patients to evaluate unexplained CKD, it reveals nonspecific tubulointerstitial fibrosis [59].

ADTKD-MUC1 should be considered in a young individual presenting with CKD in addition to the following:

●A strong family history of kidney disease in a pattern that is suggestive of autosomal dominant inheritance

●A bland urinary sediment with little or no proteinuria

●The absence of symptoms associated with UMOD or REN mutations, such as gout in patients with UMOD mutations or anemia and hyperkalemia in patients with REN mutations

Confirm with genetic testing of the MUC1 gene and other diagnostic techniques — At present, a clinically approved (Clinical Laboratory Improvement Amendments [CLIA]-approved) genetic test for ADTD-MUC1 is available through the Broad Institute of Harvard Medical School and the Massachusetts Institute of Technology. The clinically approved test only identifies the cytosine insertion, the most common mutation found in ADTKD-MUC1. It is now also possible to identify the mutated frameshift protein found in ADTKD-MUC1 within urinary cells [4] and in kidney biopsy specimens [4,60]. This testing provides a promising means of establishing a diagnosis in patients thought to have ADTKD-MUC1 but in whom no cytosine insertion is found by clinical genetic testing. In addition, other mutations, all resulting in the creation of the same frameshift protein, have been identified using novel genetic techniques.

For information on obtaining clinical genetic testing for ADTKD-MUC1 from the Broad Institute or immunohistochemical testing of urinary smears, please contact [email protected].

Differential diagnosis of ADTKD-MUC1 — Patients with MUC1 mutations, similar to those with ADTKD-UMOD and ADTKD-REN, have a bland urinary sediment, which differentiates them from hereditary glomerulopathies such as Alport syndrome or congenital focal segmental glomerulosclerosis. The autosomal dominant inheritance differentiates ADTKD-MUC1 from forms of nephronophthisis, which are autosomal recessive and associated with early-onset ESKD (usually occurring in the teenage years or early 20s).

●(See "Clinical manifestations, diagnosis, and treatment of Alport syndrome (hereditary nephritis)".)

●(See "Focal segmental glomerulosclerosis: Epidemiology, classification, clinical features, and diagnosis".)

●(See "Clinical manifestations, diagnosis, and treatment of nephronophthisis".)

ADTKD-MUC1 is differentiated from ADTKD-UMOD because hyperuricemia and precocious gout are seen in many family members with ADTKD-UMOD but not in patients with ADTKD-MUC1. Individuals with ADTKD-MUC1 do not have the childhood anemia, hyperkalemia, and hyperuricemia seen with ADTKD-REN.

Treatment of ADTKD-MUC1 — There is no specific therapy for patients with ADTKD-MUC1. Care is supportive with appropriate referral for kidney transplantation, as in other forms of CKD. (See "Overview of the management of chronic kidney disease in adults".)

The management of other manifestations of CKD, such as anemia and hyperphosphatemia, and the treatment of ESKD is similar to that in patients with other forms of CKD. (See "Overview of the management of chronic kidney disease in adults".)

Patients with MUC1 mutations are good candidates for kidney transplantation since the disease does not recur in the transplanted kidney. Family members of patients with ADTKD-MUC1 should undergo genetic testing prior to kidney donation, even if they appear to have normal kidney function.

OTHER CAUSES OF ADTKD — A minority of families are found to be negative for MUC1, UMOD, and REN mutations. These families can undergo further analysis at an academic center specializing in MUC1 kidney disease for other mutations that may occur in the MUC1 gene. Affected families may then undergo whole-exome analysis to identify the genetic cause of kidney disease.

In addition, there are several rarer causes of ADTKD that are listed for completeness:

●Hepatocyte nuclear factor-1-beta (HNF1B) mutations have a very variable presentation [61], with some individuals carrying a mutation being asymptomatic, while other family members may suffer from a number of symptoms. Common findings include renal cysts, maturity onset diabetes of youth, hyperuricemia, hypomagnesemia, asymptomatic elevations in liver function tests, and renal anomalies such as cystic kidneys, unilateral renal agenesis, and chronic kidney disease (CKD). Some individuals present with hypouricosuric hyperuricemia, bland urinary sediment, and CKD. A key to the diagnosis is a careful and extensive family history for all possible manifestations and recognition that the parent of an affected child may be unaffected, while other family members have manifestations. Definitive diagnosis can be made by genetic analysis at commercial genetic laboratories.

•(See "Renal hypodysplasia", section on 'Genetic disorders'.)

•(See "Classification of diabetes mellitus and genetic diabetic syndromes", section on 'Hepatocyte nuclear factor-1-beta'.)

•(See "Hypomagnesemia: Causes of hypomagnesemia", section on 'Hepatocyte nuclear factor-1-beta gene mutations'.)

●Mutations in Sec61 translocon alpha 1 subunit (SEC61A1) also result in autosomal dominant tubulointerstitial kidney disease. Associated symptoms in one family included neutropenia and abscess formation and, in another family, growth retardation and anemia [62].

●Alagille syndrome is an autosomal dominant condition due to mutations in jagged 1 (JAG1) or notch 2 (NOTCH2). The most common manifestations of this syndrome include cardiac anomalies (pulmonic stenosis and tetralogy of Fallot), a distinct facies with prominent forehead and a pointed chin, and ocular abnormalities. Patients may also develop CKD without proteinuria leading to dialysis [63].

•(See "Causes of cholestasis in neonates and young infants", section on 'Alagille syndrome'.)

•(See "Inherited disorders associated with conjugated hyperbilirubinemia", section on 'Alagille syndrome'.)

●Hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome, also known as Barakat syndrome, is another autosomal dominant condition. Patients may have cystic kidneys, renal hypoplasia, and nephrocalcinosis. Approximately 10 percent proceed to end-stage kidney disease (ESKD) [64]. (See "Etiology of hypocalcemia in infants and children", section on 'Genetic mechanisms'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a group of uncommon genetic disorders characterized by progressive decline in kidney function and autosomal dominant inheritance. The key to identification is the presence of chronic kidney disease (CKD) in a parent and a child, both with a bland urinary sediment.

●ADTKD is characterized by the following features (see 'Overview and classification' above):

•Autosomal dominant inheritance.

•Slowly progressive kidney disease, with impaired kidney function typically appearing in the teenage years, and end-stage kidney disease (ESKD) onset that is highly variable, usually between the ages of 20 and 70 years.

•A bland urine sediment with no or minimal proteinuria.

•Medullary cysts may be seen on kidney ultrasonography but are not present in most cases.

●There are three genetic conditions that account for almost all cases of ADTKD, all of which meet the above criteria, and each of which has distinguishing characteristics (table 1):

•ADTKD due to UMOD mutations (ADTKD-UMOD) – ADTKD-UMOD, also known as uromodulin kidney disease (UKD), is caused by mutations in the UMOD gene encoding uromodulin (also known as Tamm-Horsfall protein). In addition to progressive CKD, this disorder is characterized by gout occurring at an early age (sometimes even in the teenage years) in many, but not all, affected individuals. ADTKD-UMOD is the most common subtype, accounting for the majority of cases of ADTKD. (See 'ADTKD due to mutations in the UMOD gene (ADTKD-UMOD)' above.)

•ADTKD due to REN mutations (ADTKD-REN) – ADTKD-REN is due to mutations in the REN gene encoding renin. Mutations in the REN promoter or prosegment present in childhood with decreased kidney function, low or low-normal blood pressures, anemia that occurs before the onset of CKD, mild hyperkalemia, and hyperuricemia. Patients with mutations in the mature renin peptide present in an identical manner to individuals with ADTKD-UMOD. ADTKD-REN is the rarest subtype of ADTKD. (See 'ADTKD due to mutations in the REN gene (ADTKD-REN)' above.)

•ADTKD due to MUC1 mutations (ADTKD-MUC1) – ADTKD-MUC1, also known as mucin-1 kidney disease (MKD), is caused by mutations in the MUC1 gene encoding mucin-1 and is associated with progressive CKD but no other distinguishing characteristics (ie, no precocious gout, childhood anemia, hypotension, or hyperkalemia). It accounts for approximately 30 percent of ADTKD. (See 'ADTKD due to mutations in the MUC1 gene (ADTKD-MUC1)' above.)

●A presumptive diagnosis of ADTKD-UMOD can be made based upon clinical manifestations (early-onset gout, unexplained CKD with a bland urine) and a strong family history of gout or CKD. The diagnosis is confirmed through genetic testing. There is no specific therapy available for ADTKD-UMOD. Treatment includes management of gout with a xanthine oxidase inhibitor as well as management of progressive CKD. Many such patients are treated with a xanthine oxidase inhibitor, even if they do not have gout, for prevention of progressive CKD, although data supporting this approach are weak. (See 'Diagnosis of ADTKD-UMOD' above and 'Treatment of ADTKD-UMOD' above.)

●A presumptive diagnosis of ADTKD-REN can be made based upon clinical manifestations (a child with unexplained anemia, a history of acute kidney injury, or CKD in conjunction with hyperkalemia, low or low-normal blood pressure, and hyperuricemia) and a strong family history of CKD. The diagnosis is confirmed through genetic testing. Treatment of anemia in ADTKD-REN depends upon whether or not the patient is symptomatic. Some affected individuals do well with a hemoglobin between 10 and 11 g/dL and do not require therapy. Other patients who are symptomatic and/or have lower hemoglobin levels should be treated with erythropoietin. Symptomatic low blood pressure and hyperkalemia respond well to treatment with fludrocortisone. A high-sodium diet can be employed as an alternative to fludrocortisone therapy. It is also important to avoid the use of nonsteroidal antiinflammatory drugs and to avoid placing these patients on a low-sodium diet. (See 'Diagnosis of ADTKD-REN' above and 'Treatment of ADTKD-REN' above.)

●The diagnosis of ADTKD-MUC1 is suspected based upon the presence of unexplained CKD plus a strong family history of CKD, and it can be confirmed through genetic testing. There is no specific therapy for patients with ADTKD-MUC1. Care is supportive with appropriate referral for kidney transplantation, as in other forms of CKD. (See 'Diagnosis of ADTKD-MUC1' above and 'Treatment of ADTKD-MUC1' above.)

ADDITIONAL INFORMATION AND CORRESPONDENCE — The author is interested in studying the clinical and genetic characteristics of individuals with these disorders and would be willing to discuss potential cases with the reader. Author e-mail: [email protected].