Annual rate of growth in total liver and kidney volume is a novel parameter when assessing symptom burden from liver cysts in autosomal dominant polycystic kidney disease (ADPKD)

Introduction: Liver cysts are the most common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD), occurring in over 85% of affected individuals. There is controversy as to whether liver volume in ADPKD is associated with increased frequency of ADPKD-specific symptoms. Alternatively, the relationship between the rate of growth of liver volume over time and symptoms has never been investigated. Thus, this study aimed to determine if the annual growth rate of combined height-adjusted liver and total kidney volume (htTKLV) impacted the frequency of symptoms reported by patients in the HALT Progression Polycystic Kidney Disease Study A. Methods: HALT Progression Polycystic Kidney Disease Study A was a multicenter, randomized, placebo-controlled trial. Inclusion was limited to hypertensive ADPKD subjects aged 15-49 years with an estimated glomerular filtration rate (eGFR) greater than 60 mL/min. Each subject had MRI assessments of total kidney and liver volume and screening for the presence of 35 pre-specified symptoms at regular intervals, including baseline and 48 months. The annual growth rate of htTKLV over 48 months was calculated for each subject, ranked into ascending order and divided into 3 groups. The frequencies of the symptoms in each of the tertiles were then determined, and logistic regression analysis was performed, controlling for age, sex, and eGFR. A similar method was also performed for htTKLV at 48 months. Results: The analysis included 416 subjects, 89% of which had liver cysts. Tertile 1 was 62% female with a mean age of 38.1 years, mean rate of growth of -0.003 mL/m/year; mean htTKLV of 1697 mL/m (range: 938- 4602), and mean eGFR of 80 mL/min. Tertile 2 was 41% female, 37.3 years, 0.03 mL/m/ year, 2003 mL/m (1065-5357) and 79 mL/min, respectively. Tertile 3 was 44% female, 36.7 years, 0.07 mL/m/year, 2529 mL/m (range: 930-8883), and 77 mL/min, respectively. When compared to htTKLV, annual growth rate of htTKLV shared an equal association with liver cyst pain, was more strongly associated with shortness of breath with exertion, and was uniquely associated with three additional symptoms: cough, sore throat, and lower extremity edema (Tables 1 and 2). Conclusions: This study demonstrates that the combined growth rate of liver and kidney cysts in ADPKD associates with symptoms of the disease in a related but distinct manner when compared to liver and kidney volume. Interestingly, compression of adjacent structures may explain those symptoms associated with rate of growth, whereas organ weight may explain those symptoms associated with volume. Thus, the annual growth rate of htTKLV should be utilized in future studies attempting to associate symptoms with liver cyst burden in ADPKD; failure to account for it in previous studies may explain the discordant data seen thus far. (Table Presented).