Clinical Guidance

In ARPKD-PKHD1 several genotype-phenotype correlations have been observed based on class of the pathogenic variant and location within the fibrocystin protein (see and , respectively) . Importantly, no statistically significant differences for kidney survival (i.e., time to onset of KRT) were found during childhood and adolescence when comparing subgroups of individuals stratified according to their molecular diagnosis .

Table 3a.

Autosomal Recessive Polycystic Kidney Disease – PKHD1: Genotype-Phenotype Correlations by Variant Class

PKHD1 Variant Class | Genotype-Phenotype Correlation | Comment

Source: GeneReviews — "Autosomal Recessive Polycystic Kidney Disease–PKHD1"

Diagnostic Criteria

Consensus expert recommendations for the clinical diagnosis of autosomal recessive polycystic kidney disease (ARPKD) were published in 2014 .

Suggestive Findings

Autosomal recessive polycystic kidney disease – PKHD1 (ARPKD-PKHD1) should be suspected in probands with the following age-related clinical and ultrasonographic findings at presentation and family history. Note: (1) Ultrasonography is the imaging method of choice for assessing the kidneys prenatally and in all pediatric age groups because it is cost-effective, painless, widely available, and does not require radiation or sedation. (2) Kidney biopsies should not be performed to diagnose ARPKD.

Perinatal Presentation (prenatal to age 4 weeks)

Kidney

Source: GeneReviews — "Autosomal Recessive Polycystic Kidney Disease–PKHD1"

Differential Diagnosis

Autosomal recessive polycystic kidney disease (ARPKD) belongs to a group of congenital hepatorenal fibrocystic syndromes and is a cause of significant kidney- and liver-related morbidity and mortality in children. Among individuals with ARPKD, PKHD1 is the most commonly involved gene. ARPKD caused by pathogenic variants in PKHD1 (i.e., ARPKD-PKHD1) must be distinguished from the following :

Source: GeneReviews — "Autosomal Recessive Polycystic Kidney Disease–PKHD1"

Management Guidelines

Consensus expert recommendations for the management of autosomal recessive polycystic kidney disease (ARPKD) and clinical practice recommendations for perinatal cystic kidney diseases have been published . The following recommendations are based on these published practice guidelines, additional data, and the authors' personal experience managing individuals with this disorder. Note: Because some data on ARPKD predates the understanding of its heterogeneous genetic causes, information in this section is based on both study cohorts with ARPKD in general and cohorts with ARPKD-PKHD1 .

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ARPKD-PKHD1, the following evaluations are recommended (if not already performed as part of the evaluation that led to the diagnosis).

Perinatal and infantile presentation (prenatal to age 1 year)

Source: GeneReviews — "Autosomal Recessive Polycystic Kidney Disease–PKHD1"

Clinical Guidance

Individuals with hypertension should avoid sympathomimetic agents. In general, unless the clinical situation warrants their use, avoid known nephrotoxic agents including nonsteroidal anti-inflammatory drugs (NSAIDs) and aminoglycosides. High-salt diet, smoking, and obesity should be avoided. Minimize use of potentially hepatotoxic agents (e.g., acetaminophen doses 30 mg/kg/day, herbal supplements, and alcohol). While work in cell and animal models suggests that caffeine, theophylline-like agents, and calcium channel blockers may exacerbate the formation and growth of renal cysts, this hypothesis has not been rigorously studied in individuals with ARPKD. Thus, the clinical relevance of these observations remains unclear.

Source: GeneReviews — "Autosomal Recessive Polycystic Kidney Disease–PKHD1"

Therapies Under Investigation

Recent studies in two animal models of ARPKD suggest that tesevatinib (TSV), a unique multikinase inhibitor, markedly slows the progression of both renal cystic disease and hepatobiliary disease . These data, in addition to safety data generated by a Phase I/II multicenter clinical trial of TSV (also called KD-019) in ADPKD (NCT01559363), have led to an initial Phase I/II multicenter clinical trial of TSV in infants and children with ARPKD. To date, results have not been published. Two multinational open-label Phase III trials on the effects of tolvaptan in ARPKD-PKHD1 have been initiated . One trial focuses on children with a high risk for KRT in the first year of life based on recently established risk patterns for dialysis dependency.

Source: GeneReviews — "Autosomal Recessive Polycystic Kidney Disease–PKHD1"

Surveillance Guidelines

To monitor existing manifestations in all individuals regardless of age of initial presentation, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended.

Source: GeneReviews — "Autosomal Recessive Polycystic Kidney Disease–PKHD1"