Clinical characteristics: The two clinical presentations observed in autosomal dominant tubulointerstitial kidney disease – REN (ADTKD-REN) correlate with the renin protein domains affected by the causative REN variants.

1. Childhood/adolescent onset, the more common presentation (caused by REN variants encoding the signal peptide or prosegment domains), is characterized by decreased estimated glomerular filtration rate, acidosis, hyperkalemia, and anemia early in life, followed by slowly progressive chronic kidney disease (CKD) and gout.

2. Adult onset, the less common presentation (caused by REN variants encoding the mature renin peptide), is characterized by gout or mild slowly progressive CKD, beginning in the third decade. Anemia, hyperkalemia, and acidemia do not occur.

Diagnosis/testing: The diagnosis of ADTKD-REN is established in a proband with suggestive findings and a heterozygous pathogenic variant in REN identified by molecular genetic testing.

Management: Treatment of manifestations: Care by a nephrologist as soon as ADTKD-REN is diagnosed. In persons with childhood/adolescent-onset disease, anemia may be treated with erythropoietin. Fludrocortisone (a pharmacologic analog of aldosterone) corrects aldosterone deficiency (and associated mild hypotension), hyperkalemia, and acidemia. Treatment with fludrocortisone prior to the development of Stage 3 CKD may be indicated.

In all persons with ADTKD-REN, lifelong treatment of hyperuricemia with allopurinol prevents gout. Renal replacement therapies (such as hemodialysis and peritoneal dialysis) can replace renal function, but are associated with potential complications. Kidney transplantation is curative, as the transplanted kidney does not develop the disease.

Surveillance: Childhood/adolescent-onset disease: measurement of hemoglobin concentration and serum concentration of uric acid, bicarbonate, and creatinine at least every six months starting at the time of diagnosis. Adult-onset disease: similar laboratory testing every six to 12 months, depending on the level of kidney function.

Agents/circumstances to avoid: Nonsteroidal anti-inflammatory drugs, especially in persons who are dehydrated. Angiotensin-converting enzyme inhibitors could aggravate the underlying relative renin deficit. Volume depletion and dehydration as well as high meat and seafood intake may worsen hyperuricemia and exacerbate gout. Affected individuals should not be on the low-sodium diet typically used in the treatment of CKD.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status (by molecular genetic testing for the familial REN pathogenic variant) of apparently asymptomatic at-risk relatives, as CKD – one of the primary manifestations of this disorder – is often asymptomatic. Diagnosis of an affected individual as early as possible allows prompt initiation of treatment and awareness of agents/circumstances to avoid. Particularly important are: (1) children and adolescents because of their increased risk for acute kidney injury, anemia, acidemia, and hyperuricemia and gout; and (2) relatives interested in donating a kidney to an affected family member.

Genetic counseling: ADTKD-REN is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% chance of inheriting the REN pathogenic variant. Once the REN pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible.