Therapies effective in animal models of PKD that may be effective in human PKD include angiotensin blockade (ACE inhibitors and ARBs), lipid-lowering medications (HMG CoA reductase inhibitors), vasopressin-2 receptor antagonists (V2RA; renal only), EGFR inhibitors (renal and liver), and dietary modifications (low protein, high soy protein, flaxseed oil, fish oil).30,31
Studies indicate that deficiency of fibrocystin causes enhanced downstream effects of EGFR tyrosine kinase, making EGFR-specific tyrosine kinase inhibitors (EGFR-TKIs) candidates for therapy (). EGFR-TKIs are small molecules that competitively bind to the intracellular tyrosine kinase domain of EGFR, preventing receptor autophosphorylation.32
EGFR-TKIs, which can be administered orally, have been shown to retard the progression of kidney and liver disease in murine models of ARPKD, reducing renal cyst size and preserving renal function.21
This class of drugs appears relatively safe in adult patients with cancer; dose-dependent diarrhea and skin rash are the most common side effects.32
However, the potential side effects of EGFR-TKIs in the pediatric age group are not known. Specifically, we do not know the long-term effects on growth and maturation of cells with a high mitotic index, such as gastrointestinal tract epithelia. Skin biopsy might potentially be used to monitor tissue levels of EGFR-TKIs.
V2RAs decrease intracellular cAMP within renal collecting duct cells via the stimulatory G protein, Gs31
(). Preclinical trials with a particular V2RA, OPC-31260, on the pck
rat, the pcy
mouse, and the Pkd2WS25
mouse resulted in decreased renal cAMP levels, renal cyst volume, kidney weight, plasma BUN, mitotic and apoptotic indexes, and renal fibrosis volume.31
Preclinical trials with OPC-41061 (human V2RA) produced similar effects in the pck
V2RA therapy might prove beneficial for ameliorating or preventing the renal cysts in ARPKD but not for the bile duct disease, since there are no V2 receptors in the liver. Tolerance to the effects of these agents with chronic use is a possibility. Another concern is that V2RA may result in decreased renal medullary blood flow or dehydration, especially in infants. On the other hand, potential benefits of V2RAs may be that they might contribute to the control of systemic hypertension via down-regulation of ENaC and slow the progression of chronic renal insufficiency. Another therapeutic approach might be to decrease cAMP using agonists to inhibitory G protein (Gi) such as somatostatin31
(). The potential advantages and disadvantages of somatostatin treatment have not been studied.
Inhibition of c-Src, which is a component of the intra-cellular pathways common to EGFR and cAMP signaling, has the potential to be a most effective treatment33
(). Some preclinical studies of c-Src inhibition in the pck
rat have demonstrated amelioration of both renal and hepatic abnormalities.33
Further studies are required to explore the safety and efficacy of this approach.
Currently, we do not know how the EGFR receptor, water channels, and ion transporters are mistargeted to their ectopic locations. Identification of intermediary trafficking pathways involved in this mislocalization may provide additional new targets for treatment.
It appears premature to initiate a clinical therapeutic trial for ARPKD. Outcome parameters must be defined but might include measurements of renal functional reserve, tubular function (including maximal concentrating ability), ambulatory blood pressure, urinary biomarkers of fibrosis, high-resolution renal ultrasonography, and magnetic resonance imaging. For congenital hepatic fibrosis and portal hypertension, one might follow the platelet count, leukocyte count, spleen size, elastography of the liver, endoscopy in selected patients, upright oxygen saturation as a measure of hepatopulmonary syndrome, and bile duct imaging with magnetic resonance cholangiography.