Background: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive inherited disease based on pathogenic variants of at least 26 known BBS genes and is primarily characterized by hyperphagia-associated early-onset obesity, renal anomalies that lead to renal failure in 25% of patients, retinal degeneration, hypogonadism, and polydactyly. Management of obesity and associated metabolic disorders such as metabolic syndrome, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD), remains a challenge in patients after kidney transplantation (KTx) with BBS. The melanocortin-4 receptor agonist setmelanotide compensates for upstream gene defects in the brain leptin-melanocortin pathway and reduces hyperphagia and obesity in selected monogenetic obesity forms and Bardet-Biedl syndrome (BBS). No data on its use after KTx is actually available.
Objective: We present the impact of setmelanotide treatment in two KTx patients with BBS within the first six months after starting therapy.
Results: The first patient is a 5 year old girl (compound heterozygous pathogenic variant in BBS10 gene; BMI z-score 3.91), who received a pre-emptive KTx at the age of 3 years. After 6 months of setmelanotide treatment BMI z-score decreased by 0.61 points. GFR was slightly decreasing from 72.9 before treatment start to 59.3 ml/min/1.73m2 six months later.
The second patient is a 20 year old woman (homozygous pathogenic variant in BBS16 gene; BMI z-score 4.21), who received a preemptive living kidney donation from her mother at the age of 11. After 6 months of setmelanotide treatment BMI z-score decreased by 0.33 points. GFR was stable with 41.4 before treatment start and 48.0 ml/min/1.73 m2 six months later.
In both patients, hyperphagia score decreased close to zero and hepatic steatosis improved to normal values from grade 2 resp. grade 1 steatosis (measured by attenuation imaging with initial ATI values of 0.74 resp. 0.68 dB/cm/MHz) and both subjectively reported better mobility. Apart from hyperpigmentation, there were no significant side effects.
Conclusion: Setmelanotide treatment in patients with BBS and after KTx offers an effective approach for significant reduction of BMI, hyperphagia and MASLD. Future studies will have to confirm these findings in larger cohorts.