Individuals heterozygous for ALG8 protein-truncating variants are at increased risk of a mild cystic kidney disease.

ALG8 protein-truncating variants (PTVs) have previously been described in patients with polycystic liver disease and in some cases cystic kidney disease. Given a lack of well-controlled studies, we determined whether individuals heterozygous for ALG8 PTVs are at increased risk of cystic kidney disease in a large, unselected health system-based observational cohort linked to electronic health records in Pennsylvania (Geisinger-Regeneron DiscovEHR MyCode study). Out of 174,172 patients, 236 were identified with ALG8 PTVs. Using ICD-based outcomes, patients with these variants were significantly at increased risk of having any kidney/liver cyst diagnosis (Odds Ratio 2.42, 95% confidence interval: 1.53-3.85), cystic kidney disease (3.03, 1.26-7.31), and nephrolithiasis (1.89, 1.96-2.97). To confirm this finding, blinded radiology review of computed tomography and magnetic resonance imaging studies was completed in a matched cohort of 52 thirty-plus year old ALG8 PTV heterozygotes and related non-heterozygotes. ALG8 PTV heterozygotes were significantly more likely to have cystic kidney disease, defined as four or more kidney cysts (57.7% vs. 7.7%), or bilateral kidney cysts (69.2% vs. 15.4%), but not one or more liver cyst (11.5% vs. 7.7%). In publicly available UK Biobank data, ALG8 PTV heterozygotes were at significantly increased risk of ICD code N28 (other disorders of kidney/ureter) (3.85% vs. 1.33%). ALG8 PTVs were not associated with chronic kidney disease or kidney failure in the MyCode study or the UK Biobank data. Thus, PTVs in ALG8 result in increased risk of a mild cystic kidney disease phenotype.

Strategies to Treat Obesity in Patients With CKD.

Obesity prevalence continues to increase worldwide, accompanied by a rising tide of hypertension, diabetes, and chronic kidney disease (CKD). Although body mass index is typically used to assess obesity in clinical practice, altered body composition (eg, reduced muscle mass and increased visceral adiposity) are common among patients with CKD. Weight loss achieved through behavioral modification or medications reduces albuminuria and in some cases slows the decline in estimated glomerular filtration rate. Use of medications that promote weight loss with favorable cardiovascular risk profiles should be promoted, particularly in patients with type 2 diabetes, obesity, and CKD. For those who fail to achieve weight loss through lifestyle modification, bariatric surgery should be considered because observational studies have shown reductions in risk for estimated glomerular filtration rate decline and kidney failure. Uncertainty persists on the risk to benefit ratio of intentional weight loss in patients with kidney failure due to the lack of prospective trials and limitations of observational data. Regardless, sleeve gastrectomy is increasingly being used for patients with kidney failure and severe obesity, with success in achieving sustained weight loss, improved access to kidney transplantation, and favorable posttransplantation outcomes. More research is needed assessing long-term cardiovascular and kidney outcomes of most weight loss medications.