#6359 DAPAGLIFLOZIN TREATMENT IN AUTOSOMAL DOMINANT ALPORT SYNDROME (ADAS)
Authors: Carrillo Isabel Galan , Gatius Serena , Galvez Ana Cristina Rodenas 
Published: June 2023

Abstract

Background and Aims
Alport Syndrome (AS; ORPHA 63) is one of the most frequent hereditary kidney diseases (HKD). Its autosomal dominant form due to COL4A3-4 heterozygous mutations is being increasingly diagnosed thanks to the generalization of genetic studies. Since there is no curative treatment for the disease, management is based on drugs that slow its progression, mainly RAAS inhibitors. The SGLT2 inhibitor Dapagliflozin has demonstrated to slow chronic kidney disease (CKD) progression by decreasing proteinuria, however very few ADAS patients were included in its clinical trial. Our aim is to analyze whether dapagliflozin is associated with a decrease in proteinuria in ADAS patients.

Method
In this prospective observational study, we analyzed 12 ADAS patients that started dapagliflozin due to proteinuria in spite of maximum tolerated RAAS inhibitor treatment and eGFR &gt; 25 ml/min/1.73 m2. We analyzed diabetes and hypertension presence (and its control), weight changes, possible adverse effects and laboratory variables before and after treatment initiation (Cr, eGFR, K, uric acid, albuminuria, proteinuria).

Results
During a mean follow-up period of 7±4 months, we observed 12 patients, 5 (41.7%) male, 61±10 years old. 2 (33.3%) had type 4 diabetes, 2 (16.7%) had impaired fasting glucose (IFG), 11 had hypertension diagnosis, 1 patient had obesity (BMI 36) and other 7 were overweight (mean BMI 28±2). 9 patients had the higher dose of an RAASi, the other three couldn’t achieved it because of hypotension events. 3 patients also took an antagonist of mineralocorticoid. Only one had another diuretic prescription (furosemide 40 mg/d). Mean proteinuria prior to Dapagliflozin initiation was 1.0±0.4 gr/d, protein-to-creatinine ratio (UPCR) 1275±635 mg/g and albumin-to-creatinine ratio (ACR) 784±418 mg/g. 10 out of the 12 patients had some grade of decrease in their proteinuria, with a mean decrease of 416±183 mg/g of UPCR (p = 0,046) and a mean decrease of 292±178 mg/g of ACR (p = 0,020). Looking only at patients without diabetes, they had a lesser degree of estimated glucosuria than diabetes patients, but maintained the improvement in proteinuria quite similar to the overall group (mean ACR improvement 244±95 mg/g). All patients had optimal blood pressure control, and there were no significant body weight losses. Mean eGFR previous to SGLT2i initiation was 50±22 ml/min/1.73 m2, and after 45±19 ml/min/1.73 m2 (p = 0,008), with a mean fall of 8±8%. There were no differences in potassium levels (p = 0,079) and a decrease of uric acid levels (6.7±1.3 mg/dl vs 6.0±1.4 mg/dl, p = 0,016). The two patients who didn’t achieve an improvement in their proteinuria were not diabetic patients and had optimal blood pressure control, one of them had a weight gain of two kilograms, and the other had no weight changes. They had a similar eGFR fall to the overall group. Possible adverse events were monitored, although we didn’t find any of them: no urine tract infections, hyperpotassemia, acute kidney injury, dehydration. No patient required treatment suspension. Two of them required a withdrawal in their other diabetes medications and the one on furosemide tried a lesser dose but had to increase it again.

Conclusion
Slower progression drugs are the main treatment of ADAS nowadays. Dapagliflozin had demonstrated its beneficial effects in other proteinuric CKD, but it hasn’t been well studied in ADAS. In our sample, it seems to achieve a proteinuria improvement without significant adverse effects and known bearable eGFR fall. Large studies must be considered to determine its beneficial use in a long-time basis.