Nephrolithiasis in Cystic Fibrosis: A Gastrointestinal Perspective on Mechanisms and Management

In the current era of cystic fibrosis (CF) transmembrane conductance regulator (CFTR)-directed therapies (modulators), people with CF have significant improvement in pulmonary disease burden and overall survival. Extrapulmonary complications, including those affecting the gastrointestinal and renal systems, are gaining attention. Nephrolithiasis is increasingly recognized as a significant comorbidity in CF. The mechanisms underlying nephrolithiasis in CF are multifactorial and closely associated with altered gastrointestinal milieu in CF. Overt or residual fat malabsorption (due to exocrine pancreatic insufficiency along with other causes such as altered bile salt handling, acidic intestinal pH), and increased intestinal permeability collectively enhance enteric oxalate absorption. Renal stones in CF tend to present at a younger age, are associated with higher recurrence rates, and require more frequent procedural interventions compared with the general population with nephrolithiasis. With the increased survival in the post modulator era, the burden of renal complications in CF is expected to grow. There is lack of CF-specific nephrolithiasis guidelines and more studies on this topic are needed. Also, given the paucity of pediatric studies, literature from adults can be carefully inferred. Clinicians should educate people with CF on preventative strategies such as optimizing pancreatic enzyme replacement therapy, enhancing hydration, nutritional management strategies such as optimizing dietary calcium intake particularly when consuming high-oxalate foods, managing hypocitraturia, and minimization of nephrotoxic medication exposures. Multidisciplinary team approach is recommended to optimize outcomes from nephrolithiasis. In this review, the epidemiology, pathogenic mechanisms, and clinical management of nephrolithiasis in CF, with an emphasis on early-life contributors and opportunities for improved prevention in CF management are detailed.