Autosomal Dominant Tubulointerstitial Kidney Disease

Etiology

Autosomal dominant tubulointerstitial kidney disease is a rare renal disorder caused by variable mutations in different genes. As discussed previously, at least five different gene mutations have been observed to result in this group of disorders. An autosomal dominant inheritance pattern inherits this disorder. MUC1 gene encodes a mucin-1 protein, UMOD gene encodes uromodulin protein (previously known as Tamm-Horsfall protein), HNF1B gene encodes hepatocyte nuclear factor 1 beta, REN gene encodes renin, and SEC61A1 gene encodes translocon subunit SEC61A.[5] The details of the pathogenesis underlying these genetic mutations will be discussed in the pathophysiology section of this article.

Epidemiology

Since autosomal dominant tubulointerstitial kidney disease is a rare and recently identified disorder, the exact prevalence has not been determined, neither in the United States of America nor worldwide.[5] There is no difference in the incidence rate between males and females because this condition is inherited in an autosomal dominant manner. The child, either sex, has a 50% chance of inheriting the mutated gene. The mean age of end-stage renal disease (ESRD) is 45 years old, but the range is variable, starting from 17 years old up to 75 years old.[6] No geographic or sex differences are reported.

ADTKD-UMOD may present in adolescence with gout; hyperuricemia is highly prevalent. Chronic kidney disease (CKD) is often diagnosed in late adolescence or early adulthood. ADTKD-REN could present with hyperkalemia, anemia, and CKD as early as infancy. ADTKD-MUC1 patients generally develop CKD in their early twenties. ADTKD-HNF1B could present with genitourinary abnormalities in childhood, gout or diabetes in the teenage years, and CKD in the third decade of life. Extrarenal abnormalities are also possible. All subtypes usually lead to progressive ESRD, occurring typically between 25 and 70 years of age, and those with gout experience its onset between the age range of 3 and 51 years.[7][8] For instance, a study in Ireland reported that ADTKD was the underlying cause of ESRD in at least 0.54% of patients.[5]

ADTKD is believed to be one of the commonest monogenic forms of renal disease, and overall it accounts for around 5% of all monogenic causes of CKD.[9] The prevalence of the various types of ADTKD has not been widely studied; however, ADTKD-UMOD and ADTKD-MUC1 are perhaps more frequently encountered than ADTKD due to mutations in HNF1B or REN. In many studies, ADTKD-UMOD was the most common genetic kidney disease after ADPKD, with a population prevalence of 9 per million.[10]

Pathophysiology

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

In ADTKD-UMOD, endoplasmic reticulum stress may occur due to the retention of the mutant uromodulin (mUMOD) protein inside the endoplasmic reticulum (ER) of tubular epithelial cells in the thick ascending limb of the renal tubules. This will lead to tubular cell death, decreased cellular release, urinary excretion of the wild-type protein, and chronic kidney disease.[11][12] Additionally, the defective biogenesis and intracellular uromodulin transport affect the Na-K-2Cl cotransporter resulting in defective urinary concentration and mild volume depletion, secondarily increasing proximal reabsorption of uric acid, leading to hyperuricemia.[13][14] About two-thirds of the mutations that cause ADTKD-UMOD (mUMOD) involve cysteine residues, and no mutations are reported resulting in loss of transcription or truncation. All these findings imply the important role of the mutant uromodulin (mUMOD) protein in the pathophysiology of ADTKD-UMOD.[15]

In autosomal dominant tubulointerstitial kidney disease-SEC61A1, this condition is associated with missense mutations in SEC61A1. It is responsible for encoding the alpha subunit of endoplasmatic reticular membrane translocon SEC61. Many studies confirmed that the normal function of the SEC61 complex and its translocon is essential for normal kidney development.[16]

In autosomal dominant tubulointerstitial kidney disease-REN, the disease is mainly caused by non-truncating mutations in the first exon of the REN gene that affect the protein leader peptide residues. The type of the mutation is either missense changes like (L16R, W10R, W17R, and C20R) or an in-frame deletion (L16del). Another study identified a new novel renin mutation in exon 10 of the REN gene. These mutations can lead to endoplasmic reticulum stress and unfolded protein response activation, leading to improper renal development.[17]

In autosomal dominant tubulointerstitial kidney disease-HNF1B, the HNF1B gene has an essential role in early embryonic development. It is also known as transcription factor-2 (TCF2). This gene is located on chromosome 17q12, which codes for protein hepatocyte nuclear factor 1 homeobox B. Since HNF1B is expressed in the body's variable tissues like the kidney, liver, pancreas, and genitourinary tract, this may explain the variable clinical presentations of the HNF1B-related disorders. It was found that loss of HNF1b could induce epithelial-mesenchymal transition. This transition will ultimately lead to kidney fibrosis by up-regulation of the expression of transforming growth factor−β ligands in renal epithelial cells.[18]

Histopathology

Histology of autosomal dominant tubulointerstitial kidney disease shows interstitial fibrosis with normal glomeruli and tubular atrophy. Lamellation and thickening of tubular basement membranes are frequent findings.[3][19][7][20] Tubular dilatation could be seen, and tubular microcysts have been observed. Immunofluorescence for immunoglobulins and complement is negative. Electron microscopy provides little or no additional information; however, it may reveal the accumulation of mUMOD in the ER of thick ascending loop cells.[21] The following is the list of changes that have been reported in association with various types of ADTKD:

• Interstitial fibrosis
• Tubular atrophy
• Thickening and lamellation of tubular basement membranes
• Possibly tubular dilatation (microcysts)
• Negative immunofluorescence for complement and immunoglobulins

History and Physical

Autosomal dominant tubulointerstitial kidney disease is a group of inherited kidney disorders caused by different gene mutations that share the same histological findings. Occasionally, nephronophthisis may appear in young individuals with features suggestive of ADTKD; however, autosomal recessive inheritance differentiates it from ADTKD3.[22] The rate of decline of the estimated glomerular filtration rate is exceedingly variable in ADTKD-MUC1, ADTKD-UMOD, and ADTKD-HNF1B.[19][7] The urinary sediment is generally normal, but microhematuria can occasionally be seen. Proteinuria is either mild or completely absent. Glomerular involvement has been rarely found, such as in glomerulocystic disease and secondary focal segmental glomerulosclerosis.[23] The initially normal kidney size starts to decline with advancing disease. Patients generally have no history of hypertension preceding impaired renal function. With progression, blood pressure could increase, but typically only modestly.

The clinical manifestations are widely variable and gene-dependent. The following is a discussion that encompasses the most likely observed clinical features with each gene mutation:

ADTKD-MUC1 was previously called medullary cystic kidney disease type 1. This disease is characterized by progressive tubulointerstitial fibrosis that ultimately leads to ESRD. ESRD typically starts in adulthood, but it may occur at any age, from 20 years old to 70 years old. There are no other systemic manifestations. Since this disease is transmitted in an autosomal dominant manner, a family history of chronic renal insufficiency is an important key point to figuring out this disease.[24]

ADTKD-UMOD was known historically as familial juvenile hyperuricemic nephropathy type 1 (FJHN1), uromodulin-associated kidney disease (UMOD-associated kidney disease), and medullary cystic kidney disease type 2 (MCKD2). The clinical manifestation is slowly progressive chronic kidney disease, usually noticed in the teen years, and progression to ESRD between the fourth and seventh decades of life. Other important clinical features are gout and hyperuricemia, resulting from inappropriately decreased fractional urate excretion that usually occurs as early as the teenage years.[25]

ADTKD-REN was known previously as familial juvenile hyperuricemic nephropathy type 2 (FJHN2). This disease is characterized by hypo-proliferative anemia with a low hemoglobin concentration in the first decade of life. The clinical symptoms of CKD and hyperuricemia start in childhood or adolescence. This condition is also characterized by bland urinary sediment, mildly elevated serum potassium concentration, slightly decreased blood pressure, polyuria, and low plasma renin activity. Patients usually progress to ESRD in their fourth to sixth decade of life.[17]

ADTKD-SEC61A1 is a newly discovered disease caused by a mutation in SEC61A1. Since it is a new disease, the whole clinical picture is not conspicuous. To date, very few families have been identified with this disorder. In one family, dysplastic kidneys, anemia, and intrauterine growth retardation were present. In another family, anemia, neutropenia with abscess formation, and chronic kidney disease were documented.[6]

A mutation in the TCF2 gene causes ADTKD-HNF1B. The kidney and the pancreas express the homeodomain-containing transcription factors hepatocyte nuclear factor 1 alpha and 1 beta. Research has identified that mutations in this gene may cause the maturity-onset diabetes of youth (MODY), but further studies explicate that mutations in this gene may also lead to renal manifestations. The varied clinical manifestations and the fact that these clinical manifestations are not present consistently in all affected family members made diagnosing this condition difficult. The non-renal manifestations may include maturity-onset diabetes mellitus of the young, abnormal liver function tests of unclear etiology, genito-urinary tract malformations, and hyperuricemia with gout. In adolescence, hypomagnesemia may occur in some individuals. The renal manifestations are common in adulthood and often involve numerous renal cysts, congenital solitary kidney, congenital anomalies of the kidney and urinary tract system, renal dysplasia, and hypoplastic kidneys.[26][6]

Evaluation

Since autosomal dominant tubulointerstitial kidney disease is a rare condition and difficult to predict, it is prudent for health care providers to consider this disease, especially if the patient has signs and symptoms of renal failure at a young age with a family history of end-stage renal disease. However, even with limited knowledge, nephrologists can obtain the diagnosis and improve patient care with the help of the following criteria:

Criteria for Suspecting a Diagnosis of ADTKD

• Family history is compatible with the autosomal dominant pattern of inheritance of CKD in line with clinical characteristics (as mentioned above).
• In the absence of a family history of CKD in line with clinical characteristics, demonstration of relevant histology on renal biopsy or extrarenal features compatible with HNF1B mutation, or history of early-onset hyperuricemia with or without gout.

Criteria for Establishing the Diagnosis of ADTKD

• Family history is compatible with the autosomal dominant pattern of inheritance of CKD in line with clinical characteristics (as mentioned above) and relevant histology in at least one affected relative. (Of note, it is not possible to establish a definitive diagnosis by kidney biopsy alone)or
• Demonstration of mutation in at least one of the four genes in the patient or at least one family member

The variable rate of decline in renal function with the mean age of end-stage renal disease is approximately 45 years, but the range is 17 years up to 75 years.[6]

In ADTKD-MUC1, genetic diagnosis is not straightforward. It is essential to know that testing for the MUC1 gene mutation is not a direct mutational analysis, and this test is not performed at commercial clinical laboratories at this time. A recent study was conducted to detect MUC1fs protein by immunostaining the MUC1fs protein on the epithelial tissues and the urinary cell smears in individuals with ADTKD-MUC1, and the result is promising. Still, it is not readily available at the clinical lab yet.[27]

In ADTKD-UMOD, the diagnosis may be made based on the appropriate and relevant clinical scenario and the knowledge that another family member has been identified with a UMOD mutation on genetic testing. However, uromodulin genetic analysis is readily available at commercial clinical laboratories.[25]

In ADTKD-REN, genetic analysis of the REN gene should always be used to make the diagnosis. When the renin and aldosterone are stimulated, the levels are in the low normal range in most patients, making this type of measurement inadequate for making the diagnosis.[6]

In ADTKD-HNF1B, this condition's clinical scenario is widely variable, with different renal and extrarenal clinical manifestations. The cost-effective NGS-based strategies allow rapid and simultaneous sequencing of several genes, including HNF1B.[18]

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

Treatment / Management

Treatment of autosomal dominant tubulointerstitial kidney disease mainly focuses on managing the symptoms associated with each type of disease and slowing down the progression to end-stage renal disease. It seems reasonable that potentially affected family members be well managed for other risk factors known to worsen or cause CKD, such as arterial hypertension, diabetes, smoking, and obesity, and annual kidney function testing is necessary. There are few treatment options for children at risk for UMOD- or MUC1-associated diseases. On the contrary, minors with HNF1B- and REN-associated diseases are likely to improve from early treatment. Affected individuals should typically be treated according to established CKD guidance.[28] The followings are the most important management options for each sub-type of the disease:(A1)

Regarding ADTKD-UMOD, allopurinol or febuxostat are the best treatment options for gout and hyperuricemia. Patients should be encouraged to take one of these medications as soon as gout develops to prevent further gout attacks and gouty tophi. Although starting allopurinol early in life may prevent gout from developing later, the risks and benefits should be discussed thoroughly with the patient or the family if the patient is minor because allopurinol has some important side effects and severe allergic reactions.[29] It is also essential to inform all women of child-bearing age that this medication may have some teratogenic effects and should be stopped before the pregnancy.[30] As kidney disease progression is typically slow, and the UMOD mutations affect only the kidneys, these patients are excellent renal transplantation candidates.(B3)

Regarding ADTKD-MUC1, there is no specific therapy at present. Optimal therapy to manage chronic kidney disease, such as controlling blood pressure and secondary chronic kidney disease changes, are the only available treatments for this condition. As progression to end-stage renal disease is at a slow rate, and the fact that this condition affects only the kidney, these patients are excellent candidates for renal transplantation.[6]

For ADTKD-REN, there are several treatment options currently available. As these patients are in mild hypovolemia with a low renin state, it is essential to avoid the low sodium diet, commonly recommended for chronic kidney disease. These patients are prone to develop acute kidney injury on a low sodium diet due to worsening hypotension. Hyperkalemia and mild hypotension could be treated by fludrocortisone or a higher sodium content diet. Fludrocortisone may correct hyperkalemia and hypotension and improve hyperuricemia but does not ameliorate hemoglobin levels. Fludrocortisone may slow chronic kidney disease progression by lowering renin production (both the normal and the mutated renin).[6]

For ADTKD-HNF1B, there is no specific therapy for this disease. The treatment is mainly supportive of chronic kidney disease. Allopurinol or febuxostat should be considered for patients with early-onset gout to prevent tophus development and urate accumulation. Screening for abnormal liver function tests, hyperglycemia, hypomagnesemia, and hyperuricemia is an essential part of the management to prevent further complications. Renal ultrasound should be performed to evaluate renal morphologic abnormalities.[31][6](B3)

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

It is important to know that patients with ADTKD are excellent candidates for kidney transplantation, particularly if there are no extra-renal manifestations.[6]

Differential Diagnosis

Autosomal dominant tubulointerstitial kidney disease is a congenital renal anomaly that ultimately leads to end-stage renal disease. This condition is inherited in an autosomal dominant manner. It is essential to exclude other congenital renal diseases before making the diagnosis.[24][25] The following consists of the most likely differential diagnosis of this condition:

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

Prognosis

Although autosomal dominant tubulointerstitial kidney disease is considered benign, most cases will ultimately develop end-stage renal disease. To improve the prognosis, the treatment should focus on slowing the progression to ESRD. The mean age at which the ESRD develops is variable, and it depends on the form of the disease; it could be at a younger age, as in the teens or later in adulthood. Lifelong treatment could control the symptoms associated with chronic kidney disease, but it will not treat the underlying cause. It was documented that renal transplantation may have an excellent prognosis, especially if the kidney is the only organ affected.[6][29]

Complications

ESRD is the most critical complication associated with autosomal dominant tubulointerstitial kidney disease. ESRD leads to variable health issues that should be addressed thoroughly and appropriately treated.[6][29] The followings encompass the most likely complications associated with ESRD:

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

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

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