Friday, March 16, 2018

Progress in Prognostic Risk Stratification in Autosomal Dominant Polycystic Kidney Disease

Educating patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) is unique, as patients typically witness the course of the disease in their affected family members. This is often a parent, but due to the complexities of life including difficult family dynamics, estrangement, or early fatality from other causes (ie. trauma, cancer, cardiovascular disease), it may also be a sibling, parent’s siblings, or a grandparent. At first assessment, they commonly ask “Am I going to end up like them?” Contrarily, up to 15% of patients present with no family history (PMID: 28522688), and the delivery of an ADPKD diagnosis and prognosis can be devastating and seemingly out of the blue.

Relatively recently, many nephrologists felt there was no therapeutic options to offer patients with ADPKD, resulting in therapeutic nihilism until patients reached advanced stages of chronic kidney disease. Following TEMPO (PMID: 23121377) and REPRISE (PMID: 29105594), which reported significant reductions in the rate of GFR decline and kidney growth but with significant cost and side effects, and awaiting an FDA decision projected for April 2018, nephrologists will increasingly need to decide whether “the juice is worth the squeeze”.

Precision medicine aims to identify the best patient for a particular treatment using information from patient history, examination, and bloodwork, as well as incorporating more advanced imaging, genetics, and biomarkers, as well as patient preferences and values. Providing an accurate prognosis to patients is important for selecting the right interventions, but also for life planning for the patient and resource planning for the system.

Diagnosis can be made with ultrasound, especially in those with family history and age over 30, which has allowed time for cysts to grow. Assessment with Magnetic Resonance Imaging (MRI) including calculation of age and height adjusted Total Kidney Volume ( is the best method for ADPKD risk stratification (PMID: 24904092) and has been approved by the FDA as a prognostic enrichment biomarker for clinical trial design ( However, the terms of use include a specific disclaimer against use in clinical care. Furthermore, the economic ramifications of MRI screening of ADPKD patients needs to be considered.

                                                      From: Ekser andRigotti NEJM 2010

Genetic testing is increasingly available, and while costs are falling and our knowledge of the prognostic implications of mutation type is increasing, recommendations remain against widespread testing of all patients (PMID: 25786098). Cases where genetic testing may be of particular importance include: cases with unclear diagnosis (ie. loss of kidney function without enlargement); cases without family history; severe early onset disease; families with intrafamilial discordance; atypical lopsided or unilateral appearance; suspicion of another syndromic presentation (ie. nephronopthosis, autosomal dominant tubulointerstitial kidney disease, tuberous sclerosis) or exclusion of disease in a young patient by checking for a known familial mutation. Nonetheless, it is now recognized that patients with truncating PKD1 mutations (large deletions, nonsense, frameshift, and canonical splice site mutations) have the worst prognosis, followed by PKD1 non-truncating mutations (including inframe insertions/deletions and missense mutations), and PKD2 mutations (PMID: 26453610). After exhaustive screens, those without mutations detected tend to have the mildest disease. However, due to a high degree of allelic heterogeneity, determining if a rare mutation is in fact causal of ADPKD in a specific patient remains far from trivial and interpretation of sequencing results requires specific training and experience.

Future work is required to specifically identify who needs what testing (imaging, genetics, or both), and what the specific benefits are of obtaining either or both types of information. It appears quite likely that those with the greatest risk of disease progression towards kidney failure have the most to gain from disease modifying therapies, especially if they are associated with a therapeutic burden. Future predictive techniques will incorporate imaging and genetics and our growing knowledge of the cyst physiology and polycystin-1 and polycystin-2, and utilize tools such as artificial intelligence, to improve precision medicine care of patients with ADPKD.

Matthew Lanktree @MattLanktree
Heritable Kidney Disease Post Doctoral Fellow
University Health Network
University of Toronto

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