Dataset Information

Systematic review on outcomes used in clinical research on autosomal recessive polycystic kidney disease-are patient-centered outcomes our blind spot?

ABSTRACT:

Background

Autosomal recessive polycystic kidney disease (ARPKD) is a rare severe hepatorenal disease. Survivors of pulmonary hypoplasia and patients with milder presentations often achieve long-term survival but frequently require kidney and/or liver transplantation.

Objective

To examine the use of clinical, surrogate and patient-centered outcomes in studies on ARPKD with special attention to core outcomes of the Standardized Outcomes in NephroloGy project for children with chronic kidney disease (SONG-Kids).

Data sources and study eligibility criteria

A systematic MEDLINE literature search identified 367 ARPKD studies published since 1990; however, of these 134 were excluded because they did not report any clinical outcomes (e.g. only histopathological, genetic, protein structure or radiological markers), 19 studies because they only included prenatal patients and 138 because they were case reports with ≤ 3 patients.

Study appraisal

Seventy-six eligible studies were examined for study type, size, intervention, and reported outcomes by organ system and type, including all SONG-kids tier 1-3 outcomes.

Participants

There were 3231 patient-reports of children and adults with ARPKD.

Results

The overwhelming majority of studies reported clinical and surrogate outcomes (75/76 (98%) and 73/76 (96%)), but only 11/76 (14%) examined patient-centered outcomes and only 2/76 (3%) used validated instruments to capture them. Of the SONG-Kids core outcomes, kidney function was reported almost universally (70/76 (92%), infection and survival in three quarters (57/76 (75%), 55/76 (72%)) and measures of life participation (including neurological impairment) only rarely and inconsistently (16/76 (21%)).

Limitations

Thirty studies (39%) were of low quality as they were either narrative case reports (n = 14, 18%) and/or patients with ARPKD were an indistinguishable subgroup (n = 18, 24%). Only 28 trials compared interventions, but none were randomized.

Conclusions and implications

Studies that reported clinical outcomes in ARPKD usually covered the core outcome domains of kidney function, infections, and survival, but measures of life participation and patient-centered outcomes are distinctly lacking and require more attention in future trials. A higher resolution version of the Graphical abstract is available as Supplementary information.

SUBMITTER: Gimpel C

PROVIDER: S-EPMC8599334 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Background and objectivesAutosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 gene. The longest open reading frame comprises 66 exons encoding polyductin or fibrocystin, a type I transmembrane protein with 4074 amino acids. Functional investigations are considerably hampered by its large size and lack of expression in tissues that are usually available for analysis such as lymphocytes or fibroblasts.Design, setting, participants, & measurementsAllegedly strong and clear-cut genotype-phenotype correlations for the type of PKHD1 mutation could be established. Thus far, practically all patients with two truncating mutations showed perinatal or neonatal demise and at least one hypomorphic missense mutation is thought to be indispensable for survival. Mutation analysis of >500 ARPKD families was performed by conventional and next-generation sequencing techniques.ResultsThis study presents four unrelated patients with ARPKD with a nonlethal, moderate clinical course despite the burden of two PKHD1 mutations expected to lead to premature termination of translation. In line with parental consanguinity, all mutations occurred in the homozygous state and segregated with the disorder in these families. To try to unravel the mechanisms that underlie this obvious contradiction, these patients were further analyzed in detail by utilizing different methods. In all cases, complex transcriptional alterations were detected. Alternative splicing patterns might disrupt a critical stoichiometric and temporal balance between different protein products and may play a crucial role in defining the phenotype of these patients.ConclusionsAlthough these findings represent rare events, they are of importance for genetic counseling and illustrate that some caution is warranted in the interpretation of mutations and their clinical significance. The authors hypothesize that expression of a minimal amount of functional protein is needed for survival of the neonatal period in ARPKD.