Clinical Guidance

In the most comprehensive report of autosomal dominant tubulointerstitial kidney disease due to REN pathogenic variants (ADTKD-REN) to date, comprising 111 individuals from 30 families, observed two clinical presentations, childhood/adolescent onset and adult onset, which correlate with the protein domains encoded by REN variants . Childhood/adolescent onset, the more common presentation, is caused by REN variants encoding the signal peptide or prosegment domains. It is characterized by decreased estimated glomerular filtration rate (eGFR), acidosis, hyperkalemia, and anemia early in life, followed by slowly progressive chronic kidney disease and gout. Some children also experience polyuria. Adult onset, the less common presentation, is caused by REN variants encoding the mature renin peptide. It is characterized by gout or mild, slowly progressive CKD, beginning in the third decade. Anemia, hyperkalemia, and acidemia do not occur. Table 4. ADTKD-REN: Comparison of Phenotypes by Genotype and Select Features

Diagnostic Criteria

Consensus clinical diagnostic criteria for autosomal dominant tubulointerstitial kidney disease due to REN pathogenic variants (ADTKD-REN) have been published (full text). Suggestive Findings ADTKD-REN should be suspected in individuals with the following clinical findings (grouped by age) and a family history consistent with autosomal dominant inheritance . Clinical Findings – Childhood/Adolescent-Onset Disease Low renin production (low to low-normal plasma renin and aldosterone levels associated with the following in most, but not all, individuals) manifesting as: • Blood pressure that is often borderline low, but usually asymptomatic • Hyperkalemia (serum potassium levels 5 mEq/L, sometimes as high as 6.5 mEq/L) in about 50% of individuals, often present from birth • Acidosis (serum bicarbonate levels between 15 and 24 mEq/L), often present from birth Hypoproliferative anemia in most affected children by age one year characterized by: • Low erythropoietin concentration • Low hemoglobin concentrations (usually 9-11 g/dL) • Low reticulocyte count relative to the hemoglobin concentration • Otherwise normal hematologic findings Hyperuricemia resulting from decreased renal excretion of uric acid: • Hyperuricemia (serum uric acid concentration 6 mg/dL) is present in 80% of affected individuals beginning in childhood. Usually, hyperuricemia in an individual with normal kidney function corresponds to a serum concentration of uric acid 1 SD above the normal value for age and sex. It is important to use age-related norms for serum urate . • Decreased fractional excretion of urinary uric acid in the vast majority of individuals with ADTKD-REN. See for reference ranges by age in individuals with normal kidney function. The fractional excretion of uric acid is usually 5% in adult men and 6% in adult women. The reduction of urate excretion can be detected in affected children with preserved renal function . Note: (1) The fractional excretion of urinary uric acid can be measured from a spot urine sample; however, a 24-hour urine collection is preferable. (2) Aspirin, diuretics, and nonsteroidal agents should be avoided during the collection. (3) Because the fractional excretion of uric acid rises above 5% as renal function worsens, this test is not sensitive in individuals who have an eGFR 70 mL/min. Table 1. Serum Uric Acid Concentration in Individuals with Normal Renal Function Age | Serum Concentration (mg/dL) Males | Females

Management Guidelines

Consensus management guidelines for autosomal dominant tubulointerstitial kidney disease due to pathogenic variants in REN (ADTKD-REN) have been published (full text).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ADTKD-REN, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Surveillance Guidelines

Childhood/adolescent-onset disease. Monitor blood pressure, serum potassium, bicarbonate, creatinine, and hemoglobin at least every six months. Adult-onset disease. Monitor blood pressure, serum potassium, bicarbonate, creatinine, and hemoglobin every six to 12 months, depending on the level of kidney function.

Source: GeneReviews — "Autosomal Dominant Tubulointerstitial Kidney Disease – REN"