Abstract: PO1631
An International Cohort Study of Mutations in RENIN Causing Autosomal Dominant Tubulointerstitial Kidney Disease
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - 2
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Bleyer, Anthony J., Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
- Zivna, Martina, Univerzita Karlova 1 lekarska fakulta, Praha, Praha, Czechia
- Kidd, Kendrah O., Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
- Papagregoriou, Gregory, University of Cyprus, Nicosia, Cyprus, Nicosia, Cyprus
- Rampoldi, Luca, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
- Abdelwahed, Mayssa, Universite de Sfax, Sfax, Tunisia
- Sinclair, Matthew R., Duke University School of Medicine, Durham, North Carolina, United States
- Trachtman, Howard, NYU School of Medicine, NY, New York, United States
- Kopel, Tal H., Universite de Montreal Faculte de Medecine, Montreal, Quebec, Canada
- Santostefano, Marisa, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
- Izzi, Claudia, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
- Laszkiewicz, Agnieszka, Laboratory of Molecular and Cellular Immunology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
- Jakubowska, Anna, Wroclaw Medical University Department and Clinic of Paediatric Nephrology, Wroclaw, Poland
- Zaidan, Mohamad, Necker Hospital; APHP; Universite de Paris, Paris, France
- Hodanova, Katerina, Univerzita Karlova 1 lekarska fakulta, Praha, Praha, Czechia
- Knebelmann, Bertrand, Necker Hospital; APHP; Universite de Paris, Paris, France
- Kmoch, Stanislav, Univerzita Karlova 1 lekarska fakulta, Praha, Praha, Czechia
Background
There have been few clinical reports of Autosomal Dominant Tubulo-interstitial Kidney Disease due to REN Mutations (ADTKD-REN), limiting clinical characterization.
Methods
We formed an international collaboration that identified and characterized 111 individuals from 30 families with heterozygous REN mutations.
Results
Sixty-nine (62%) individuals had a REN mutation in the signal peptide region (signal group), 27 (24%) in the prosegment (prosegment group), and 15 (14%) in the mature renin peptide (mature group). Laboratory investigations revealed that REN signal peptide mutations prevented recognition and translocation of preprorenin into the endoplasmic reticulum (ER), prosegment mutations led to abnormal deposition of prorenin and renin in the ER Golgi intermediate compartment (ERGIC), and mutations in mature renin led to deposition of prorenin and renin in the ER. Signal and prosegment patients were most severely affected, often presenting at <10 years (see Table 1) with anemia, hyperkalemia, and acute and chronic kidney disease. While eGFR was approximately 50 ml/min in children < 10 years, eGFR remained stable until age 20, with mean age of end-stage kidney disease (ESKD) >50 in this cohort. The mean hemoglobin level in children <10 y not receiving erythropoietin was 9.6±1.04 g/dL (7.4-13.8 g/dl), which improved with erythropoietin administration. The serum potassium values decreased and bicarbonate values increased in 9 patients taking fludrocortisone (4.77±0.55 mEq/L vs. 4.37±0.54 mEq/L, p< 0.01 and 23.7±3.5 mEq/L vs. 25.9±2.3 mEq/L, p=0.003). Patients with mutations in mature renin presented 〉20y with gout and chronic kidney disease.
Conclusion
There are 3 subtypes of heterozygous REN mutations that are pathophysiologically and clinically distinct.
Patient Characteristics
| Characteristics | Signal | Prosegment | Mature | p value |
| n | 69 (62%) | 27(24%) | 15(14%) | |
| Age presentation <10 y | 23(39%) | 11(61%) | 0 | 0.003 |
| Age at presentation (mean±s.d.) | 19.7±15.7 | 22.4±20.2 | 37.0±12.4 | <0.01 |
| Anemia as child | 39/43(91%) | 11/16(69%) | 0 | <0.001 |
| Gout | 14/55(25%) | 13/20(65%) | 9/14(64%) | 0.74 |
| Age ESKD (mean±s.d.) | 53.1±10.6 | 50.8±17.6 | 63.6±7.6 | <0.01 |
Funding
- Private Foundation Support