For 20 years, Dr. Pei and his team have made significant research contribution to improve the clinical care of patients with ADPKD. Highlights of some of our published work are shown below:
(1) Elucidating molecular genetic mechanism of cyst formation
Previous studies suggested that individual cyst formation in ADPKD arises from inactivation of both copies of the PKD1 gene within single epithelial cells through bloodline and somatic mutations, but these data were inconclusive. To address this issue, we screened kidney and liver cysts with patients with known bloodline PKD2 mutations and identified somatic PKD2 mutations in ~75% of the cysts – a detection rate that matched the sensitivity of the detection assay used. These data provide the most definitive evidence in support of the "two-hit" model of ADPKD (Nat Genet 25: 143-4, 2000). Under this model, somatic PKD mutations constitute the rate-limiting step for individual cyst formation. The major implication of these findings is that genetic and environmental factors are likely to influence the kidney somatic mutation burden and modify the severity of ADPKD.
(2) Refining genotype-phenotype correlation in ADPKD
We conducted the largest PKD2 genotype-phenotype correlation study to date (J Am Soc Nephrol 14: 1164-74, 2003), documented a significant heritability for Ccr and age at ESRD in a large cohort of PKD1 families (J Am Soc Nephrol 16: 755-62, 2005), developed clinical predictors for the ADPKD mutated gene types (J Am Soc Nephrol 20: 1833-8, 2009), and identified variations at the DKK3 locus as potential modifiers for PKD1 renal disease severity (J Am Soc Nephrol 21: 1510-20, 2010). We also found strong evidence that some missense PKD1 mutations may function as “hypomorphic alleles” associated with mild renal disease, indistinguishable from PKD2 (Kidney Int 81: 412-7, 2012). This class of mutations may account for up to ~30% of PKD1 mutations and their characterization in the Toronto Genetic Epidemiology Study of PKD (TGESP) has allowed us to refine and develop mutation-based clinical prognostication in ADPKD (J Am Soc Nephrol 27: 1861-68, 2016).
(3) Defining imaging-based diagnostic criteria for ADPKD
We have developed unified ultrasound diagnosis criteria for ADPKD which are now widely used by clinicians world-wide (J Am Soc Nephrol 20: 205-12, 2009). However, due to the milder forms of ADPKD (i.e. PKD1 non-truncating and PKD2 mutations) disease exclusion by conventional ultrasound in the at-risk subjects is not possible until age 40 years. To address this limitation, we have recently derived highly sensitive and specific criteria for disease exclusion in at-risk subjects at age 18-40 years by high-resolution ultrasound or MRI (J Am Soc Nephrol 26: 746-53, 2015).
(4) Systems biology of human PKD1 renal cysts
By global gene expression profiling, we generated a detailed map of aberrantly activated gene pathways in PKD1 renal cysts and identified several novel molecular targets which may modulate cyst growth (Hum Molec Genet 18: 2328-43, 2009). This work has led to a number of collaborations for pre-clinical studies of novel therapeutics for PKD1 (Proc Nat Acad Sci USA 108: 18067-72, 2011; Nature Med 19: 488-93, 2013; J Am Soc Nephrol 25: 1737-48, 2014).
(1) Disease complications and healthcare costs of ADPKD
To advance personalized medicine we are currently studying a large cohort of patients with ADPKD in Ontario to define their kidney and non-kidney related complications by mutation-based prognostic class. At the time, we will also evaluate their healthcare costs to identify specific clinical scenarios where a novel but expensive disease-modifying drug (including Tolvaptan) is both justified to offset the healthcare costs associated with disease progression. Such knowledge will be critically needed to inform healthcare decision makers how best to provide coverage for novel but expensive therapy in ADPKD.
(2) Kidney and liver cyst ablation by foam sclerotherapy
Total kidney volume (TKV) in adult patients with ADPKD expands on average ~5% per year and is a strong predictor for progression to end-stage kidney failure. Large cysts within the kidney are particularly detrimental by impeding the blood flow to and blocking urine flow from the kidney filters. Over the past two years, we have developed an experimental therapy (a.k.a. foam sclerotherapy) to reduce TKV by ablation of one or more large (>5cm) kidney cysts. This procedure is performed in an operation room by an interventional radiologist under ultrasound guidance and i.v. sedation. This treatment is effective in decreasing TKV and safe with minimal risk of infection or bleeding. We will be conducting a pilot trial to evaluate the effects of cyst ablation on kidney blood flow and filtration rate and define the specific patient group(s) most likely to benefit. The same procedure can also be used to help relieve the “mass effect” in patients with severe polycystic liver disease.
(3) Developing new treatment by drug repurposing
More than 10 commonly used drugs with good safety profile for other diseases have been identified to attenuate the cystic kidney disease in mouse models of ADPKD. One example is Metformin which is used for treatment of type 2 diabetes mellitus. We have developed an experimental program to evaluate and identify two to three more promising re-purposed drugs from these pre-clinical studies to be tested in pilot clinical trials. This work is partly supported by a grant from the Canadian Institutes of Health Research (CIHR) Chronic Kidney Disease (CKD) Patient Oriented Research Strategy (SPOR) program and represents an active area of our current research.