Elsevier

Kidney International

Volume 98, Issue 6, December 2020, Pages 1589-1604
Kidney International

Clinical Investigation
An international cohort study of autosomal dominant tubulointerstitial kidney disease due to REN mutations identifies distinct clinical subtypes

https://doi.org/10.1016/j.kint.2020.06.041Get rights and content

There have been few clinical or scientific reports of autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN), limiting characterization. To further study this, we formed an international cohort characterizing 111 individuals from 30 families with both clinical and laboratory findings. Sixty-nine individuals had a REN mutation in the signal peptide region (signal group), 27 in the prosegment (prosegment group), and 15 in the mature renin peptide (mature group). Signal group patients were most severely affected, presenting at a mean age of 19.7 years, with the prosegment group presenting at 22.4 years, and the mature group at 37 years. Anemia was present in childhood in 91% in the signal group, 69% prosegment, and none of the mature group. REN signal peptide mutations reduced hydrophobicity of the signal peptide, which is necessary for recognition and translocation across the endoplasmic reticulum, leading to aberrant delivery of preprorenin into the cytoplasm. REN mutations in the prosegment led to deposition of prorenin and renin in the endoplasmic reticulum-Golgi intermediate compartment and decreased prorenin secretion. Mutations in mature renin led to deposition of the mutant prorenin in the endoplasmic reticulum, similar to patients with ADTKD-UMOD, with a rate of progression to end stage kidney disease (63.6 years) that was significantly slower vs. the signal (53.1 years) and prosegment groups (50.8 years) (significant hazard ratio 0.367). Thus, clinical and laboratory studies revealed subtypes of ADTKD-REN that are pathophysiologically, diagnostically, and clinically distinct.

Section snippets

Results

Of the 111 individuals from 30 families (Table 1, and Supplementary Figures S1 and S2), 69 (62%) individuals had a mutation in the signal peptide, 27 (24%) in the prosegment, and 15 (14%) in the mature renin peptide. A mutation in p.S45N was identified in 1 individual with ADTKD of unknown cause. This mutation did not segregate with disease and was determined to be nonpathogenic; it was included as a control for laboratory investigations. While searching variant databases, we noticed 2

Discussion

In this work we describe distinct clinical and pathophysiologic differences (Figure 10) in signal, prosegment, and mature peptide mutations of the REN gene in a cohort of 111 patients from 30 families with ADTKD-REN.

Patients with mutations in the signal peptide region were the most severely affected. One third of the patients presented before 10 years of age, with 10% having acute kidney injury and 13% presenting with anemia, acidosis, and kidney failure. The mean age of presentation was lower

Methods

This investigation was approved by the institutional review boards of the participating centers and was carried out in accordance with the Declaration of Helsinki.

Disclosure

All the authors declared no competing interests.

Acknowledgments

The authors thank all participating patients and families, and the referring physicians. We also thank Dr. Heike Göbel (Institute of Pathology, University Hospital of Cologne, Cologne, Germany) and Dr. Helmut Hopfer (Institute of Pathology, University Hospital Basel, Basel, Switzerland) for providing renal sections. This study was supported by a grant from the Ministry of Health of the Czech Republic (NV17-29786A) and by institutional programs of Charles University in Prague, Czech Republic

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      Nevertheless, a recent international cohort study on clinical characteristics of 111 ADTKD-REN patients reported that approximately 70% of the patients presented to medical institutions for chronic kidney disease or gout.21 According to this report, childhood anemia was present in 75.8% of the patients but its severity was relatively mild; mean hemoglobin levels were 9.6, 10.1, and 10.5 g/dl for ages <10 years, 10 to <15 years, and 15 to <20 years, respectively.21 Although hypotension was not reported in the article, the severity of hyperkalemia was mild and the mean serum potassium level in patients who were not taking fludrocortisone was 4.8 mEq/l.21 Childhood anemia, hypotension, or hyperkalemia may often be overlooked, and they are not always specific to ADRKD-REN; thus, we did not exclude participants with these findings.

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