Kerri McGreal

The polycystin-1 (PC1), polycystin-2 (PC2) and fibrocystin proteins, the respective products of the PKD1, PKD2 and PKHD1 genes, are abundant in urinary exosome-like vesicles (ELVs) where they form the polycystin complex (PCC). ELVs are 100 nm diameter membrane vesicles shed into the urine by the cells lining the nephron. Using MS/MS analysis of ELVs from individuals with PKD1 mutations and controls, we show that in addition to the well-described GPS/GAIN cleavage event in PC1 at 3048 aa and the proprotein convertase cleavage (PPC) event in fibrocystin at 3616 aa, there are multiple other cleavage events in these proteins. The C-terminal 11 transmembrane portion of PC1 undergoes three cleavage events in vivo. The absence of peptides from the C-terminal cytoplasmic tail of fibrocystin implies a cleavage event close to its single TM domain prior to loading onto the ELVs. There is also evidence that the C-terminal tail of PC2 is also cleaved in ELVs. Native gel analysis of the PCC shows that the entire complex is > 2 MDa in size and that N-terminal GPS/GAIN cleaved PC1 and PPC cleaved fibrocystin ectodomains can be released under non-reducing conditions and resolve at 300 kDa. This paper shows that the three major human cystogene proteins are detectable in human urinary ELVs and that all three undergo post-translational proteolytic processing. Human urinary ELVs may be a useful source of material in the search for proteins that interact with the PCC.

BACKGROUND: Hyponatremia is a common electrolyte imbalance that clinicians face on a regular basis. SUMMARY: This review aims to discuss four current challenges that can arise when diagnosing and treating hyponatremia: low solute intake, heart failure, exercise-associated hyponatremia, and mild chronic hyponatremia. Low solute intake in a person who already has a urinary concentrating defect will lead to increased retention of free water. The free water retention will cause or worsen hyponatremia that is already present. Low solute intake is overlooked in patients with other disease processes that can cause hyponatremia, such as liver disease or heart failure. Heart failure and hyponatremia present their own set of challenges specifically with treatment as there are limited options. The newer class of aquaretics allows for the short-term treatment of hyponatremia. Exercise-associated hyponatremia is a phenomenon that has been described in ultra-endurance athletes. This happens when a person drinks a significant amount of water while exercising in the setting of antidiuretic hormone production from prolonged exercise. This acute drop in sodium must be treated with hypertonic saline. The term asymptomatic mild chronic hyponatremia is no longer valid. Mild chronic hyponatremia carries an increased risk of falls and fractures, specifically in the elderly populations. KEY MESSAGE: In summary, hyponatremia is a multifaceted disease and presents many challenges for physicians treating it.

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is a progressive genetic kidney disease. Studies of ADPKD presented results using different outcome measures. We aimed to summarize outcomes reported in ADPKD studies, including composite outcomes. Methods: We conducted a systematic review of published studies that included patients with ADPKD and measured kidney-related outcomes. We searched published databases and included all studies regardless of design with at least 100 participants for observational studies. We excluded studies that were limited to dialysis, transplant, or pregnancy outcomes in patients with ADPKD. Results: analyses, and 94 observational studies). We identified 214 different outcomes, and we categorized them into the 24 main outcome domains. In addition, the review identified 13 articles that reported 9 different composite outcomes. Conclusion: The finding highlights the inconsistency in the outcomes reported by researchers and how they are measured in ADPKD studies. The variability in the outcomes reported supports the need to standardize outcomes in ADPKD studies.

Key Points Twenty-seven percent of patients with autosomal dominant polycystic kidney disease discontinued tolvaptan in a real-world cohort in the midwestern United States. Most patients maintained tolvaptan on lower doses than trials, and a minority tolerated above the 45 mg ( am )/15 mg ( pm ) starting dosage. Adverse effects, specifically aquaretic side effects, strongly influenced tolvaptan tolerability, dosage titration, and discontinuation. Background Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent genetic kidney disease leading to kidney failure. Tolvaptan, a vasopressin V2 receptor antagonist, is the only medication approved by the US Food and Drug Administration for slowing kidney growth in individuals with rapidly progressive ADPKD, but its long-term tolerability and effective implementation has yet to be studied, particularly in real-world clinical settings within the United States. Methods This retrospective cohort study examined adults with ADPKD treated with tolvaptan at the University of Kansas Medical Center and the University of Iowa Hospitals & Clinics from May 2018 to April 2023. Data on demographics, clinical characteristics, tolvaptan dosage, and treatment duration were collected from electronic health records for an average follow-up duration of 28.2 months (interquartile range: 8.5–47.1 months). The study focused on examining tolvaptan dosage trends, treatment discontinuation reasons, and the impact of aquaretic side effects on dosage and adherence. Results Of 134 patients, 27% stopped tolvaptan during the observational period, with 10.4% of the cohort withdrawing from treatment due to intolerance of aquaretic side effects. Most patients maintained a lower tolvaptan dosage (≤45/15 mg) than in clinical trials, with two thirds of individuals who underwent dosage adjustment undergoing net decrease in dosage. Adverse effects significantly influenced and dosage decisions, presenting a potential early barrier for adherence, particularly in female patients. Conclusions The study highlights real-world challenges in the use of tolvaptan for ADPKD, particularly for side effects leading to high discontinuation rates and dosage adjustments. These findings underscore the need for standardized and improved management strategies to enhance tolerability and adherence, offering insights for future research and practice in the treatment of ADPKD with tolvaptan.