WT1-associated nephropathy refers to a kidney disease caused by abnormalities in the WT1 gene. Its main symptoms are proteinuria and nephrotic syndrome (hypoalbuminemia), potentially progressing to kidney failure. In Japan, WT1-associated nephropathy is the most common proteinuria caused by genetic mutation (alteration of genetic information). Notably, it is one of the major causes of both congenital and infantile nephrotic syndrome. Abnormalities in the WT1 gene are also associated with conditions such as Denys–Drash syndrome, Frasier syndrome, and WAGR syndrome (11p13 deletion syndrome). The type of genetic abnormalities (e.g., exon abnormalities, intron abnormalities, deletions) greatly influences the symptoms, time of onset, and coexisting or complicating conditions (diseases other than nephropathy).
Denys-Drash syndrome (exon abnormalities): Nephropathy, 46,XY disorders of sex development1, Wilms tumor2
Frasier syndrome (intron abnormalities): Nephropathy, 46,XY disorder of sex development, gonadal tumors
WAGR syndrome (deletions): Wilms tumor, aniridia3, genitourinary abnormalities4, intellectual disability
*A disorder characterized by a 46,XY karyotype, with varying degrees of masculinization issues in the gonads, internal genitalia, and external genitalia.
**A malignant tumor that develops in the kidneys.
***A congenital condition in which the iris of the eye is absent.
****Abnormalities in the structure or function of the genital organs.
Symptoms range from asymptomatic or mild swelling to rapidly progressing kidney failure, which can lead to a decline in overall health (lethargy, poor oral intake, vomiting, edema, seizures, oliguria/anuria, etc.). The onset of nephropathy and progression to kidney failure vary depending on the type of mutation.
General Timeline for the Onset and Progression of Nephropathy to Kidney Failure According to Mutation Type
| Nephropathy | Denys–Drash Syndrome (exon abnormalities) | Frasier Syndrome (intron abnormalities) | WAGR Syndrome (deletions) |
|---|---|---|---|
| Occurrence | Very common | Very common | Relatively uncommon |
| Age of Onset | From birth to ~1 year | ~5 years | Childhood to adulthood |
| Kidney Failure | Common in infancy | Common in school age | School age to adulthood |
When clinical symptoms and coexisting or complicating conditions suggest the disease, a definitive diagnosis is made by identifying mutations in the WT1 gene through genetic testing.
Currently, there is no definitive treatment for WT1-associated nephropathy. Renin-angiotensin system inhibitors may be used to suppress proteinuria, but their ability to slow the progression of kidney failure has not been proven. As kidney function declines, conditions such as hypertension, electrolyte imbalances, hyperuricemia, anemia, bone and mineral metabolism abnormalities, and acidosis (elevated blood acidity) may develop and require treatment with oral or injectable medications. When kidney function falls below 10-15% of normal, kidney replacement therapies—such as dialysis or kidney transplantation—become necessary.
Prevention and treatment of coexisting or complicating conditions are also crucial. The clinical presentation of WT1-associated nephropathy is diverse and varies among individual patients. Therefore, it is essential to accurately assess potential risks based on the type of mutation and to consider appropriate treatments and preventive measures. Treating and preventing conditions such as disorders of sex development and Wilms tumor require highly specialized expertise, and collaborative care with specialists in each field is recommended.
A. Although nationwide epidemiological studies have not yet been conducted, a survey carried out under specific conditions by our research team in 2022 identified 91 individuals with WT1-associated nephropathy in Japan.
A. The WT1 gene plays a crucial role in the development of the kidneys and urinary system, and mutations in this gene are known to cause nephropathy. In theory, WT1 gene mutations can be inherited from one parent (through autosomal dominant inheritance) or can occur spontaneously, even when neither parent carries the mutation. However, most cases are due to spontaneous mutations.
A. The onset of WT1-associated nephropathy varies. In cases of exon abnormalities, patients often experience sudden edema, lethargy, vomiting, and other systemic symptoms, which can rapidly progress to kidney failure soon after seeking medical attention. In cases of intron abnormalities, the condition is frequently asymptomatic and may be discovered incidentally during school urine screenings or in urine tests prompted by the development of Wilms tumor or genitourinary abnormalities. In cases of deletions, diagnosis may occur during a comprehensive evaluation for related conditions such as aniridia, intellectual disability, Wilms tumor, or genitourinary abnormalities.
A. Exon abnormalities can lead to early kidney failure, often requiring dialysis and eventually kidney transplantation. If kidney failure occurs, bilateral nephrectomy is recommended to prevent Wilms tumor. In cases of intron abnormalities or deletions, progression to kidney failure is slower, allowing for the management of chronic kidney disease while planning the timing of transplantation. Some patients may experience a milder course and never develop kidney failure.
A. Even if symptoms are similar, the underlying cause may not be WT1-associated nephropathy but another condition. Genetic testing is crucial for confirming WT1-associated nephropathy. Identifying the specific mutation type can help in the prediction of nephropathy progression, tumor risk, and other potential complications, aiding in prognosis and prevention.
A. WT1-associated nephropathy can be linked to a 46,XY disorder of sex development, leading to abnormalities in genitourinary development. Conditions such as hypospadias (abnormal penis morphology), cryptorchidism (undescended testes), or cases in which male chromosomes are present but external genitalia or gonads are more female-like can occur. Some individuals may appear entirely female despite having male chromosomes. In these cases, chromosomal testing is essential for determining gender, assessing or supplementing sex hormones, evaluating gonadal tumor risk, and considering surgical options for genital reconstruction.
A. Treatment is best provided at facilities with pediatric nephrologists. If kidney failure is expected, care should be received at centers equipped for pediatric dialysis and kidney transplantation. In cases of exon abnormalities, kidney failure can develop rapidly during the neonatal or infant stages. In such cases, advanced medical centers with intensive care and emergency hemodialysis are recommended. Ideally, facilities should also have specialists in endocrinology, urology, and oncology, as WT1-associated nephropathy requires expertise in these fields.
A. For patients at risk of developing Wilms tumor, ultrasound exams every three months until around age six are recommended to monitor for tumors. If kidney failure has already occurred and kidney function is lost, a preventive nephrectomy can help prevent Wilms tumor.
A. Gonadal tumors can be prevented by proactively removing the gonads. However, since gonadectomy affects fertility, specialists should carefully evaluate the need for the procedure, involving discussions with both the patient and their family. Typically, individuals with XX chromosomes have a very low risk of gonadal tumors, making removal unnecessary.
A. Kidney transplantation can restore kidney function, thereby freeing patients from dialysis, alleviating kidney failure symptoms, easing dietary and fluid restrictions, improving quality of life, and enhancing growth and development. However, it is not the end of treatment; lifelong immunosuppressive medications are needed to protect the transplanted kidney. The transplanted kidney may not function permanently, so additional transplantation or dialysis might be needed after several decades. Importantly, WT1-associated nephropathy does not recur after transplantation.
