REN-related autosomal dominant tubulointerstitial kidney disease (ORPHA:217330)
A rare autosomal dominant tubulointerstitial kidney disease (ADTKD) of childhood due to REN mutations and characterized by early onset hypoproliferative anemia, hyperuricemia, gout, and slowly progressive tubulointerstitial kidney disease.
Epidemiology
To date, approximately 35 families have been reported in the medical and scientific literature.
Clinical description
For patients with mutations in the promoter or prosegment of the REN gene, disease onset typically occurs from the first year of life, with presentation of hypoproliferative anemia and elevated serum creatinine. The anemia resolves as the child enters adolescence. Dysfunction of the renin-angiotensin system puts children at risk of volume depletion and acute kidney injury (particularly after febrile illness). Acute kidney injury typically resolves with appropriate treatment; however, baseline chronic kidney disease (CKD) may be noted. Individuals also suffer from hyperuricemia and may develop gout in their teenage years. Other occasional features include polyuria, mild hypotension and mild hyperkalemia. Kidney function slowly worsens over time with progression to end-stage kidney disease (ESKD) between 40-70 years of age. Patients with mutations in the segment of the REN gene encoding mature renin present with gout in the late teens and early twenties as well as early CKD which worsens over time and eventually requires renal replacement therapy.
Etiology
The disease is due to heterozygous missense mutations in the REN gene (1q32) and results in reduced renin biosynthesis and secretion, and intracellular accumulation of abnormal protein. These changes lead to accelerated apoptosis, nephron dropout, interstitial fibrosis, and progressive loss of kidney function.
Diagnostic methods
The diagnosis is suspected on clinical and laboratory findings including hypoproliferative anemia and hyperuricemia, decreased fractional excretion of uric acid, and evidence of slowly progressive, chronic tubulointerstitial kidney disease. A family history compatible with ADTKD may assist in diagnosis. Renal ultrasound shows normal or small-sized kidneys with no signs of cyst formation. Plasma renin levels are low. Genetic diagnosis through a multi-gene panel or whole exome sequencing provides a good option for differentiating from similar conditions.
Differential diagnosis
Renal manifestations are similar to that of nephronophthisis; however, nephronophthisis is often associated with other symptoms. For individuals with mutations in the segment encoding the mature part of the REN gene, patients present very similarly to ADTKD-UMOD.
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known mutation through molecular genetic testing.
Genetic counseling
The pattern of inheritance is autosomal dominant. The risk of inheriting the pathogenic variant is 50% in siblings and offspring of affected individuals. Penetrance is 100%, although the rate of progression of ESKD is variable. Cascade testing should be performed within families, as family members may have been misdiagnosed. Children of a parent with a REN mutation in the promoter or prosegment should have a basic metabolic panel within the first week of life, with genetic testing also performed.
Management and treatment
Children at risk should be referred to a pediatric nephrologist as early management is likely beneficial. Erythropoiesis-stimulating agents and fludrocortisone can be used for the treatment of anemia and symptomatic hypotension, respectively. Alkali supplementation can also correct metabolic acidosis but may not be as effective or as palatable as fludrocortisone. It is important to normalize serum bicarbonate to maximize growth. Fludrocortisone can potentially aggravate interstitial fibrosis and should not be used in those with declining kidney function, hypertension, hyperkalemia, or edema. Gout is typically prevented with allopurinol or febuxostat and prevention therapy is life-long; treatment with a low sodium diet and nonsteroidal anti-inflammatory drugs is contraindicated. Progression of kidney disease should be monitored by a nephrologist. As kidney disease progresses, renal replacement therapy may be required. Kidney transplantation without prior dialysis is the treatment of choice for kidney failure.
Prognosis
The prognosis is good with suitable, timely treatment. The disorder does not reoccur in transplanted kidneys.

                            Last update: 
                            June 2022


                            - Expert reviewer(s): 
                            Pr Anthony BLEYER  - Pr Stanislav KMOCH  - Dr Martina ZIVNA