Autosomal dominant tubulointerstitial kidney disease

INTRODUCTION — Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a group of uncommon genetic disorders characterized by tubular damage and interstitial fibrosis in the absence of glomerular lesions, autosomal dominant inheritance, and inevitable progression to end-stage kidney disease (ESKD).

The genetics, pathogenesis, clinical presentation, diagnosis, and treatment of the major subtypes of ADTKD are discussed in this topic.

DEFINITION 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, with a median age of 45 to 48 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) progresses. 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 previously been given a number of names (eg, familial juvenile hyperuricemic nephropathy [FJHN], medullary cystic kidney disease) that are now no longer used. We agree with the Kidney Disease: Improving Global Outcomes (KDIGO) consensus report that provides standard terminology for these conditions based on the underlying genetic defect [1]:

●ADTKD due to UMOD pathogenic variants (ADTKD-UMOD) – ADTKD-UMOD is caused by pathogenic variants 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 [2]. ADTKD-UMOD is the most common subtype, accounting for approximately 60 percent of cases of ADTKD. In the past, it was called medullary cystic kidney disease type 2 (MCKD2) and FJHN1. (See 'ADTKD due to UMOD pathogenic variants' below.)

●ADTKD due to MUC1 pathogenic variants (ADTKD-MUC1) – ADTKD-MUC1 is caused by pathogenic variants 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 [3]. In the past, this condition was called medullary cystic kidney disease type 1 (MCKD1). (See 'ADTKD due to MUC1 pathogenic variants' below.)

●ADTKD due to REN pathogenic variants (ADTKD-REN) – ADTKD-REN, which is due to pathogenic variants in the REN gene encoding renin, has two phenotypes. Patients with pathogenic variants in the portion of the REN gene encoding the signal peptide or prepropeptide have progressive CKD, low or low-normal blood pressure, anemia that occurs in childhood before the onset of CKD, mild hyperkalemia, and hyperuricemia [4,5]. Patients with pathogenic variants in the mature peptide develop gout in their late teens and ESKD at a mean age of 64 years [4]. ADTKD-REN is a less common subtype of ADTKD, accounting for approximately 5 percent of families with ADTKD. In the past, it was called familial juvenile hyperuricemic nephropathy type 2 (FJHN2). (See 'ADTKD due to REN pathogenic variants' below.)

TYPES OF ADTKD

ADTKD due to UMOD pathogenic variants — ADTKD due to mutations in the UMOD gene (ADTKD-UMOD), also known as uromodulin kidney disease (UKD), is the most common subtype of ADTKD. It is important for patients to know the name of the mutated gene, as disease names may change, be long, and be nonspecific. For this reason, patients may refer to this condition as UMOD kidney disease.

Genetics and pathogenesis of ADTKD-UMOD — ADTKD-UMOD is due to pathogenic variants in the UMOD gene on chromosome 16p12, which encodes uromodulin (Tamm-Horsfall glycoprotein) [2,6,7]. The condition is autosomal dominant: One allele makes normal uromodulin, while the other allele makes the mutated uromodulin. A catalog of UMOD mutations is available online.

Uromodulin is produced exclusively in the thick ascending limb of the loop of Henle [8]. It is an insoluble protein whose sticky, adherent properties are probably important in maintaining the water-tight integrity of the thick ascending limb [8,9]. Uromodulin also appears to facilitate intracellular trafficking of both the furosemide-sensitive Na-K-2Cl cotransporter [10] and the renal outer medullary potassium channel (ROMK) [11] to the apical surface of the thick ascending limb tubular cells (figure 1).

Approximately one-half of the pathogenic variants identified in the UMOD gene are missense pathogenic variants resulting in the deletion or addition of a cysteine residue [12]. Recurrent (founder) mutations have been described in the United Kingdom [13] and in the United States [14]. Mutant uromodulin proteins are unable to assemble properly and cannot exit the endoplasmic reticulum [15-17], resulting in accumulation of mutated uromodulin within the cells of the thick ascending limb of the loop of Henle.

Intracellular accumulation of abnormal uromodulin proteins can lead to tubular cell atrophy and death [6,15]. 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 [6,18].

The two major pathophysiologic effects of UMOD pathogenic variants are hyperuricemia and progressive chronic kidney disease (CKD):

●Hyperuricemia results from reduced urate excretion [6,19,20]. Uromodulin facilitates the intracellular trafficking of the furosemide-sensitive Na-K-2Cl transporter to the apical membrane of the thick ascending limb [21]. 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 [6,19]. Clinically, this manifests as a reduced fractional excretion of uric acid and hyperuricemia.

●Progressive CKD may be related to tubular cell death in the thick ascending limb due to intracellular accumulation of mutant uromodulin [16,22]. Kidney biopsies reveal tubulointerstitial disease characterized by interstitial fibrosis and tubular atrophy [1].

In addition to its effects on water impermeability and ion transport in the thick ascending limb, rodent and human data suggest that uromodulin protects against urinary tract infection [9,23,24] and inhibits formation of kidney calculi. However, patients with ADTKD-UMOD do not have an increased incidence of urinary tract infection [19] or kidney stones [19,25].

Clinical features of ADTKD-UMOD — De novo pathogenic variants 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. The most common clinical presentations of ADTKD-UMOD are as follows:

●Precocious gout – Gout is a common clinical feature among patients with ADTKD-UMOD, affecting approximately 65 percent in one series [26]. Whereas in the general population, gout usually occurs in middle-aged males in the setting of obesity or CKD, gout in ADTKD-UMOD often has an earlier onset. The median age of onset is approximately 25 years [27], with 25 percent of patients who develop gout doing so before age 20 years [14]. Females with ADTKD-UMOD are also frequently affected. 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.

Asymptomatic hyperuricemia is even more frequent (75 percent of patients in one series [26]). It can often be detected during childhood if testing is performed early because of a positive family history.

●Chronic kidney disease – Patients with ADTKD-UMOD develop slowly progressive CKD. They often present with a mild reduction in estimated glomerular filtration rate (eGFR), sometimes during the teenage years [17]. In a cohort of 34 children with ADTKD-UMOD, for example, the mean eGFR was 72 mL/min/1.73 m² at a mean age of 12.5 years [28]. Eleven children (32 percent) presented with stage 3 CKD at a mean age of 15 years. Kidney disease is milder in females than in males [14,29].

Kidney disease progression is highly variable between and within families. Some individuals may develop end-stage kidney disease (ESKD) in their 20s, while others may not require kidney replacement therapy until past 70 years of age. The age of onset of ESKD varies by genetic variant. In one multicenter study of 722 individuals from 249 families with 125 different UMOD variants, the median age of onset of ESKD was 47 years [14]. Patients with the UMOD p.Val93_Gly97delinsAlaAlaSerCys variant have a median age of ESKD of 52 years [13]. Some UMOD variants, such as p.Thr62Pro, are associated with an increased risk of CKD but display reduced disease severity and slower progression of CKD [30]. The median age of ESKD for individual genetic variants can be found online.

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 pathogenic variants, but other etiologies should be strongly suspected, especially if there are extrarenal manifestations.

Kidney ultrasound is typically normal, without kidney cysts [31], although kidneys may be small if CKD is advanced. If performed, a kidney biopsy reveals nonspecific tubulointerstitial fibrosis.

●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, reduced eGFR, and a positive family history).

ADTKD due to MUC1 pathogenic variants — Pathogenic variants in the MUC1 gene encoding mucin-1 cause a subtype of ADTKD referred to as ADTKD-MUC1. Patients may refer to this condition as MUC1 kidney disease. (table 1) [3].

Genetics and pathogenesis of ADTKD-MUC1 — The MUC1 gene is located on chromosome 1q21 [32-37]. Most affected families suffer from a single cytosine duplication into one variable-number tandem repeat sequence within the MUC1 coding region that leads to the creation of a specific frameshift protein [3]. New pathogenic variants 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 duplication [38]. This pathogenic variant results in an abnormal mucin-1 protein that localizes intracellularly in the loop of Henle, distal tubule, and collecting duct.

In ADTKD-MUC1, the mutated mucin-1 protein deposits within the endoplasmic reticulum Golgi intermediate compartment, leading to endoplasmic reticulum stress and slowly progressive cell death, tubular atrophy, and chronic kidney disease [3,39]. Mucin-1 is produced in the breast, skin, gastrointestinal tract, and respiratory system. It is unclear why the clinical phenotype resulting from MUC1 pathogenic variant is manifested only in the kidney [40].

Clinical features of ADTKD-MUC1

●Chronic kidney disease – The primary manifestation of the MUC1 pathogenic variant is progressive 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-UMOD and ADTKD due to REN pathogenic variants (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 pathogenic variants present in one of two ways:

•Patients present with an unexplained reduced eGFR during laboratory testing performed for other reasons, or they have unexplained progressive CKD. The urinalysis is relatively bland, without hematuria or significant proteinuria [35]. A kidney ultrasound typically reveals normal kidneys, although the kidneys may be small in size in later stages of CKD. 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 [35]. As an example, in an international cohort study of 93 individuals with MUC1 variants, the mean age of ESKD was 46 years, ranging from 25 to over 70 years; the age of ESKD was similar for males and females [27]. In another study of 72 patients from six Cypriot families, some had CKD noted during the teenage years with development of ESKD before age 30 years, while other patients had only moderate kidney function impairment into their 60s. Similar variability was noted in a study of five families from Finland [33]. 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 34 and 55. One carrier died at age 64 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 [35].

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 [35].

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 [41,42].

Kidney 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 [35]. The cysts were bilateral in approximately 60 percent of cases. Most cysts were corticomedullary or medullary, but cortical cysts were also seen.

ADTKD due to REN pathogenic variants — REN gene pathogenic variants 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 features of ADTKD-REN' below.)

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

Genetics and pathogenesis of ADTKD-REN — ADTKD-REN is caused by pathogenic variants in the REN gene on chromosome 1 that encodes renin [5,43,44]. Pathogenic variants may occur in segments of the gene encoding the promoter, prosegment, or mature renin peptide [4].

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. Of note, biallelic REN mutations cause autosomal recessive renal tubular dysgenesis, a severe disorder of renal tubular development characterized by persistent fetal anuria and pulmonary hypoplasia [45].

Renin is expressed in multiple segments of the kidney tubule, including the juxtaglomerular complex. In these cells, preprorenin is translocated into the endoplasmic reticulum, where it is converted to prorenin [46]. Some prorenin is secreted, while the remainder is targeted to lysozymes, where it is further cleaved to active renin. Pathogenic variants may occur in the segment of the gene encoding the promoter, prosegment, or mature renin peptide [4,5,43]. REN signal peptide pathogenic variants prevent translocation across the endoplasmic reticulum. REN prosegment pathogenic variants prevent proper folding of prorenin, and REN pathogenic variants in the mature renin peptide cause deposition of the mutated renin in the endoplasmic reticulum.

As the condition is autosomal dominant, a pathogenic variant 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 features of ADTKD-REN' below.)

Accumulation of preprorenin in kidney tubular cells leads to ultrastructural damage and apoptosis of these cells [5,43]. As a result, affected individuals develop CKD.

Clinical features of ADTKD-REN — The clinical features of ADTKD-REN were most comprehensively characterized in an international, multicenter study of 111 individuals from 30 families with REN pathogenic variants [4]. In general, patients with pathogenic variants in the promoter or prosegment of the REN gene present early in life, while those with pathogenic variants 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 pathogenic variants in the REN promoter or prosegment present with the following characteristics [43]:

●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 acute kidney injury (AKI) – Similar to patients taking an angiotensin-converting enzyme (ACE) inhibitor, affected patients may be at increased risk for AKI in the setting of volume depletion and/or when nonsteroidal antiinflammatory drugs (NSAIDs) are used. In several instances, children have presented with AKI in the setting of a febrile illness, nausea, and the use of NSAIDs. The AKI 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 pathogenic variants. 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'.)

●Chronic kidney disease – Patients often present with decreased 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 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 pathogenic variants 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.

Other types of ADTKD — There are several rarer causes of ADTKD that are listed for completeness:

●Hepatocyte nuclear factor-1-beta (HNF1B) pathogenic variants have a variable presentation [47], with some individuals being asymptomatic, while other family members may suffer from a number of symptoms. Common findings include kidney cysts, maturity onset diabetes of youth, hyperuricemia, hypomagnesemia, asymptomatic elevations in liver function tests, and kidney anomalies such as cystic kidneys, unilateral renal agenesis, and 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. However, in approximately 50 percent of cases, an affected individual will have a new ("de novo") mutation with a negative family history [48]. Definitive diagnosis can be made by genetic analysis at commercial genetic laboratories. (See "Renal hypodysplasia", section on 'Genetic disorders' and "Classification of diabetes mellitus and genetic diabetic syndromes", section on 'Hepatocyte nuclear factor-1-beta' and "Hypomagnesemia: Causes of hypomagnesemia", section on 'Hepatocyte nuclear factor-1-beta gene mutations' and "Gene test interpretation: HNF1B (renal cysts and diabetes syndrome gene)".)

●Pathogenic variants in Sec61 translocon alpha 1 subunit (SEC61A1) also result in ADTKD. Associated symptoms in one family included neutropenia and abscess formation and, in another family, growth retardation and anemia [49].

●Alagille syndrome is an autosomal dominant condition due to pathogenic variants 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 [50]. (See "Alagille syndrome".)

●Hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome, also known as Barakat syndrome, is another autosomal dominant condition due to mutations in GATA3. Patients may have cystic kidneys, kidney hypoplasia, and nephrocalcinosis. Approximately 10 percent proceed to ESKD [51]. (See "Etiology of hypocalcemia in infants and children", section on 'Genetic mechanisms'.)

●Patients with monoallelic pathogenic variants in DNAJB11 characteristically present with normal-sized kidneys with multiple bilateral small cysts. In one study of seven families with DNAJB11 mutations, the mean age of ESKD was 75 years (ranging from 59 to 88 years) [52]. Some patients may present similarly to patients with UMOD or MUC1 mutations, as they may have few kidney cysts and a strong family history of kidney disease.

DIAGNOSIS OF ADTKD

When to suspect ADTKD — A diagnosis of ADTKD should be suspected in any patient who presents with chronic kidney disease (CKD), a family history consistent with autosomal dominant inheritance of CKD (ie, at least one affected individual in at least two generations), and a bland urinary sediment with absent or minimal proteinuria (algorithm 1) [1].

ADTKD can also be considered in individuals with CKD and a bland urinary sediment who do not have a family history of CKD or in patients with biopsy findings of tubulointerstitial kidney disease without a primary glomerular cause. While such cases are relatively rare, they may be due to de novo mutations or a missed diagnosis of CKD in other family members.

Certain clinical features should raise suspicion for specific forms of ADTKD:

●The presence of gout and/or a strong family history of gout and inherited kidney disease is suggestive of ADTKD due to mutations in the UMOD gene (ADTKD-UMOD). (See 'Clinical features of ADTKD-UMOD' above.)

●The presence of unexplained anemia (especially in childhood), acute kidney injury, mild hyperkalemia, low or low-normal blood pressure, or hyperuricemia is suggestive of ADTKD due to REN pathogenic variants (ADTKD-REN). (See 'Clinical features of ADTKD-REN' above.)

●The absence of symptoms associated with UMOD or REN pathogenic variants, such as gout in patients with UMOD pathogenic variants or anemia and hyperkalemia in patients with REN pathogenic variants, suggests ADTKD-MUC1. (See 'Clinical features of ADTKD-MUC1' above.)

Genetic testing to confirm the diagnosis — In patients suspected of having ADTKD, the diagnosis can be confirmed with genetic testing (algorithm 1). Genetic testing is preferable to kidney biopsy in this setting.

A general discussion of clinical genetic testing including testing methods, indications for testing, ethical considerations, and practical issues is presented elsewhere. (See "Genetic testing".)

Whom to test — We perform genetic testing in all adult patients suspected of having ADTKD. However, 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. Testing for UMOD and MUC1 mutations can also be performed free of charge for individuals with ADTKD by The Rare Inherited Kidney Disease Team of Wake Forest School of Medicine (contact [email protected]).

Testing of children is generally discouraged for genetic conditions for which there is no specific treatment in childhood. Children from families with ADTKD-UMOD may wish to be tested if there is a young age of gout onset and early end-stage kidney disease (ESKD). Asymptomatic children should see a genetics counselor or specialist in ADTKD prior to genetic testing.

Pretest genetic counseling — Prior to genetic testing, patients should be apprised of the risks and benefits of genetic diagnosis, particularly if asymptomatic. Such information can be provided by a genetics counselor. (See "Genetic counseling: Family history interpretation and risk assessment".)

Briefly, benefits of genetic testing include the following:

●Many individuals simply want to know the cause of a kidney disease that has led to ESKD in many family members, often over generations. Such information will be helpful in life decisions.

●If gout has developed (in patients with ADTKD-UMOD), clinicians and patients may be more likely to consider life-long preventive therapy (eg, allopurinol or febuxostat), as gout will be highly likely to recur.

●Patients may be screened and followed for CKD.

●Patients will receive a genetic diagnosis for CKD and will not be subject to unwarranted testing such as kidney biopsies.

●Patients can participate in longitudinal cohort studies of ADTKD, leading to better understanding of this disorder.

●Patients who find out that they do not have the disease can be considered as a potential kidney donor in the future and will know that their children and progeny will not be affected.

Risks of genetic testing include the following:

●Testing may lead to an increase in anxiety. However, in one study of ADTKD, asymptomatic patients who were tested and found that they had ADTKD were overwhelmingly pleased that they underwent genetic testing [53].

●In the United States, the ability to obtain health insurance should not be affected, but the ability to obtain life insurance and disability insurance may be affected.

Preferred testing methods — The optimal approach to genetic testing for ADTKD is to perform whole exome sequencing (WES) or to order a kidney disease gene panel (algorithm 1). Several laboratories can perform this analysis; information can be found here. Testing for multiple candidate genes at one time is more cost effective and efficient than testing one gene at a time (ie, cascade testing). Since ADTKD and many other genetic causes of kidney disease are rare, and the clinician may have limited experience with the differential diagnosis of these disorders, WES or gene panels can help to identify causative genes that the clinician may not have considered. In addition, companies that provide these testing services often provide pre- and postgenetic counseling for both the provider and the patient.

Sometimes, gene panels will identify a variant of unknown significance (VUS) that could potentially be causative, but there is not yet enough clinical evidence for certainty. When ordering an inherited kidney disease gene panel, we advise requesting VUS reporting if this is an option. If a VUS is identified that could potentially be causative, this can be discussed with a genetic counselor, who is often available from the company providing the gene panel. Consultation with an expert center in the clinical condition can also be beneficial. (See "Secondary findings from genetic testing" and 'Additional information and correspondence' below.)

However, WES and existing gene panels are inadequate for the diagnosis of ADTKD-MUC1 since these methods identify only approximately 1 percent of the pathogenic variants that cause ADTKD-MUC1 [38,54]. A clinically approved (Clinical Laboratory Improvement Amendments [CLIA]-approved) genetic test for MUC1 is available from the Broad Institute of Harvard Medical School and the Massachusetts Institute of Technology through a collaboration with Wake Forest School of Medicine (contact [email protected]). This test only identifies the cytosine duplication, the most common pathogenic variant in ADTKD-MUC1. There are also centers available in Europe that provide similar MUC1 genetic testing.

It is now also possible to identify the mutated frameshift protein found in ADTKD-MUC1 within urinary cells [5] and in kidney biopsy specimens, though this is only available in a research setting [5,55]. This testing provides a promising means of establishing a diagnosis in patients thought to have ADTKD-MUC1 but in whom no cytosine duplication is found by clinical genetic testing. In addition, other pathogenic variants, all resulting in the creation of the same frameshift protein, have been identified using novel genetic techniques.

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

Screening family members — Once ADTKD has been diagnosed in a family, an effort should be made to provide family members at risk for the disorder with information about ADTKD and genetic testing. Such information can be provided by a genetics counselor or nephrologist. We believe that it is important that other family members are informed of the family diagnosis because ADTKD is rare and many family members who are affected may be undiagnosed. These family members can undergo directed genetic testing for the specific pathogenic variant found in their family.

No role for kidney biopsy — Although a kidney biopsy is sometimes performed in patients with unexplained CKD, it is not diagnostic of any form of ADTKD. 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.

A kidney biopsy is occasionally performed to evaluate CKD in affected patients when ADTKD has not been considered. In these patients, the typical finding is diffuse tubulointerstitial fibrosis [16,17,56,57].

DIFFERENTIAL DIAGNOSIS — Differentiating ADTKD from other disorders depends upon the clinical setting:

●Family history of unexplained chronic kidney disease – Examination of the urine can help to distinguish ADTKD from other childhood causes of chronic kidney disease (CKD), both genetic and acquired, which often affect the glomerulus (such as congenital focal segmental glomerulosclerosis, Alport syndrome, poststreptococcal glomerulonephritis, and immunoglobulin A nephropathy). These disorders feature blood and/or protein in the urine, whereas patients with ADTKD have a bland urinary sediment. (See "Genetics, pathogenesis, and pathology of Alport syndrome (hereditary nephritis)" and "Focal segmental glomerulosclerosis: Genetic causes".)

●Early-onset gout – 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 pathogenic variant. If the 24-hour urine collection (while the patient is off of allopurinol or febuxostat) reveals >700 mg/day of uric acid in females and >800 mg/day in males, uric acid overproduction syndromes such as HPRT deficiency should be considered. (See "Diuretic-induced hyperuricemia and gout" and "Overweight and obesity in adults: Health consequences", section on 'Gout'.)

●Medullary cysts – 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 "Kidney cystic diseases in children" and "Dent disease (X-linked recessive nephrolithiasis)" and "Clinical manifestations, diagnosis, and treatment of nephronophthisis" and "Medullary sponge kidney" and "Acquired cystic disease of the kidney in adults".)

●Progressive CKD and unexplained anemia – In addition to ADTKD due to REN pathogenic variants (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 pathogenic variants in genes encoding proteins of the primary cilium. However, these conditions can be differentiated from disease due to REN pathogenic variants based upon the following:

•Inheritance pattern – A parent of the child with a REN pathogenic variant 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 pathogenic variants, and they usually develop ESKD in their teens or early 20s, although adult-onset forms are now increasingly described [58].

TREATMENT — There is no specific therapy for patients with ADTKD. Treatment consists primarily of supportive care and management of the complications of chronic kidney disease (CKD) for all patients as well as additional measures that are specific to certain types of ADTKD.

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

Management of CKD for all patients — All patients with ADTKD should receive general measures for the management of (chronic kidney disease) CKD, including blood pressure control and treatment of complications including anemia, metabolic bone disease, metabolic acidosis, and electrolyte abnormalities. An overview of these measures is presented elsewhere. (See "Overview of the management of chronic kidney disease in adults" and "Chronic kidney disease in children: Overview of management".)

Specific considerations in the management of CKD among patients with ADTKD include the following:

●Most patients with ADTKD 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 CKD. In patients who are hypertensive and have hyperuricemia, losartan would be a preferable treatment, as it has been shown to increase urinary uric acid excretion. There is no evidence that angiotensin inhibitors slow the progression of CKD in patients with ADTKD. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Diuretic-induced hyperuricemia and gout", section on 'Benefits of angiotensin inhibition and losartan'.)

●Diuretics should be used with caution in all patients with ADTKD since these agents may worsen hyperuricemia and volume depletion. (See "Diuretic-induced hyperuricemia and gout".)

●Because patients with ADTKD due to REN pathogenic variants (ADTKD-REN) have a low-renin state with reduced activity of the renin-angiotensin system (similar to a patient receiving angiotensin-converting enzyme [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. (See 'Clinical features of ADTKD-REN' above.)

●In patients with 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 [4]. Other patients who are symptomatic and/or have lower hemoglobin levels should be treated with an erythropoiesis-stimulating agent. (See "Treatment of anemia in nondialysis chronic kidney disease", section on 'Erythropoiesis-stimulating agents'.)

Additional management of specific manifestations

Urate-lowering therapy for gout — Hyperuricemia and gout are common clinical features among patients with ADTKD due to mutations in the UMOD gene (ADTKD-UMOD) (see 'Clinical features of ADTKD-UMOD' above). Our approach to management depends upon whether or not the patient has an established diagnosis of gout:

●Patients with gout – Because patients with ADTKD-UMOD and established gout have genetically determined gout and are at high risk for future gout flares and tophus development, they qualify for pharmacologic urate-lowering therapy. The selection, initiation, and duration of pharmacologic urate-lowering therapy are similar to that for the general population with gout and are discussed in detail elsewhere. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Indications' and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Choosing the urate-lowering drug'.)

●Patients without gout – For patients with ADTKD-UMOD who have not yet developed gout, we do not typically use pharmacologic urate-lowering therapy. However, some experts may offer urate-lowering therapy to patients who have marked hyperuricemia (>9 mg/dL [>535 micromol/L]) or a strong family history of early-onset gout, although there are no data to support this approach. (See "Asymptomatic hyperuricemia", section on 'Sustained marked hyperuricemia'.)

Data on the efficacy of pharmacologic urate-lowering therapy (eg, allopurinol or febuxostat) in patients with ADTKD-UMOD are limited, and support for the use of these agents comes primarily from studies of gout in the general population. These data are presented elsewhere. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout".)

There is no high-quality evidence that urate-lowering therapy with allopurinol or febuxostat slows the rate of progression of CKD in patients with ADTKD-UMOD, although some observational studies have suggested a possible benefit with allopurinol [19,56,59-61].

Fludrocortisone for hypotension, hyperkalemia, and acidosis — Patients with ADTKD-REN tend to have low-normal blood pressures, mild hyperkalemia, and acidosis, findings consistent with a low-renin state and hyporeninemic hypoaldosteronism (type 4 renal tubular acidosis [RTA]) (see 'Clinical features of ADTKD-REN' above). Some of the patients may be symptomatic with the low blood pressure readings. As in other patients with hypotension and type 4 RTA, fludrocortisone can be used to treat such patients. Limited observational data in patients with ADTKD-REN suggest that low blood pressure and hyperkalemia respond well to treatment with fludrocortisone [43]. 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. (See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)", section on 'Treatment'.)

Fludrocortisone is also effective in treating the acidosis associated with ADTKD-REN [4], requires less pill burden, and is better tolerated than alkali administration. It is important to prevent acidosis in childhood in order to maintain normal growth.

Fludrocortisone and a high-sodium diet may also preserve kidney function, although this is hypothetical. Patients with this ADTKD-REN 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.

Kidney transplantation — Patients with ADTKD are excellent candidates for kidney transplantation since the disease does not recur in the transplanted kidney. 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 'Screening family members' above.)

COVID-19-SPECIFIC CONSIDERATIONS — Membrane-bound mucins such as mucin-1 play an important antiviral role in protecting the respiratory tract from coronavirus disease 2019 (COVID-19) infection by inhibiting COVID-19 viral entry into lung cells [62]. Emerging data suggest that patients with ADTKD-MUC1, who have an abnormal form of mucin-1 protein, may have an increased risk of death from COVID-19 [63]. In a cross-sectional analysis of a cohort of patients with ADTKD and COVID-19 during the Delta variant predominant period, ADTKD-MUC1 was associated with a 2.35-fold increased risk of contracting COVID-19 and a ninefold increased risk of death compared with ADTKD due to mutations in the UMOD gene (ADTKD-UMOD). Most, but not all, of the patients who died were long-term kidney transplant recipients.

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

●Definition and classification – Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a group of uncommon genetic disorders characterized by tubular damage and interstitial fibrosis in the absence of glomerular lesions, autosomal dominant inheritance, and inevitable progression to end-stage kidney disease (ESKD). ADTKD is characterized by the following features (see 'Definition and classification' above):

•Autosomal dominant inheritance.

•Slowly progressive kidney disease, with impaired kidney function typically appearing in the teenage years, and 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.

●Types of ADTKD – 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 pathogenic variants (ADTKD-UMOD) – ADTKD-UMOD is caused by pathogenic variants in the UMOD gene encoding uromodulin (also known as Tamm-Horsfall protein). In addition to progressive chronic kidney disease (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. (See 'ADTKD due to UMOD pathogenic variants' above.)

•ADTKD due to MUC1 pathogenic variants (ADTKD-MUC1) – ADTKD-MUC1 is caused by pathogenic variants 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 MUC1 pathogenic variants' above.)

•ADTKD due to REN pathogenic variants (ADTKD-REN) – ADTKD-REN is due to pathogenic variants in the REN gene encoding renin. Patients with variants in the portion of the REN gene encoding the signal peptide or prepropeptide have progressive CKD, low or low-normal blood pressure, anemia that occurs in childhood before the onset of CKD, mild hyperkalemia, and hyperuricemia. Patients with variants in the mature peptide develop gout in their late teens and ESKD at a mean age of 64 years. ADTKD-REN is a less common subtype of ADTKD. (See 'ADTKD due to REN pathogenic variants' above.)

●Diagnosis – A diagnosis of ADTKD should be suspected in any patient who presents with CKD, a family history consistent with autosomal dominant inheritance of CKD (ie, at least one affected individual in at least two generations), and a bland urinary sediment with absent or minimal proteinuria. The diagnosis is confirmed through genetic testing (algorithm 1). Kidney biopsy is not diagnostic of any form of ADTKD and is generally not performed as part of the routine diagnostic work-up of patients with suspected ADTKD. (See 'Diagnosis of ADTKD' above.)

●Treatment – There is no specific therapy for patients with ADTKD. Treatment consists primarily of supportive care and management of the complications of CKD for all patients as well as additional measures that are specific to certain types of ADTKD:

•All patients with ADTKD should receive general measures for the management of CKD, including blood pressure control and treatment of complications including anemia, metabolic bone disease, metabolic acidosis, and electrolyte abnormalities. These measures are discussed elsewhere. (See "Overview of the management of chronic kidney disease in adults" and "Chronic kidney disease in children: Overview of management".)

•Patients with ADTKD-UMOD who have established gout qualify for pharmacologic urate-lowering therapy. The selection, initiation, and duration of pharmacologic urate-lowering therapy are similar to that for the general population with gout and are discussed in detail elsewhere. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Indications' and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Choosing the urate-lowering drug'.)

For patients with ADTKD-UMOD who have not yet developed gout, we do not typically use pharmacologic urate-lowering therapy. However, some experts may offer urate-lowering therapy to patients who have marked hyperuricemia (>9 mg/dL [>535 micromol/L]) or a strong family history of early-onset gout, although there are no data to support this approach. (See 'Urate-lowering therapy for gout' above.)

•Patients with ADTKD-REN who have hypotension, hyperkalemia, or acidosis can be treated with fludrocortisone, as in other patients with hyporeninemic hypoaldosteronism (type 4 renal tubular acidosis). A high-sodium diet is an alternative option to fludrocortisone therapy. (See 'Fludrocortisone for hypotension, hyperkalemia, and acidosis' 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].

Additional information for patients is provided by active patient associations in the United States and in Europe.