Atypical Polycystic Kidney Disease As Defned By Imaging

Using age- and height-adjusted total kidney volume, the Mayo Clinic Imaging Classification provides a validated approach to assess the risk of chronic kidney disease (CKD) progression in autosomal dominant polycystic kidney disease (ADPKD), but requires excluding patients with atypical imaging patterns, whose clinical characteristics have been poorly defined. We report an analysis of the prevalence, clinical and genetic characteristics of patients with atypical polycystic kidney disease by imaging. Patients from the extended Toronto Genetic Epidemiology Study of Polycystic Kidney Disease recruited between 2016 and 2018 completed a standardized clinical questionnaire, kidney function assessment, genetic testing, and kidney imaging by magnetic resonance or computed tomography. We compared the prevalence, clinical features, genetics, and renal prognosis of atypical versus typical polycystic kidney disease by imaging. Forty-six of the 523 (8.8%) patients displayed atypical polycystic kidney disease by imaging; they were older (55 vs. 43 years; P< 0.001), and less likely to have a family history of ADPKD (26.1% vs. 74.6%; P< 0.001), a detectable PKD1 or PKD2 mutation (9.2% vs. 80.4%; P< 0.001), or progression to CKD stage 3 or stage 5 (P< 0.001). Patients with atypical polycystic kidney disease by imaging represent a distinct prognostic group with a low likelihood of progression to CKD.

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Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder with a prevalence of at least 1/1000 and is an important cause of end-stage kidney disease (ESKD)1–3 . Progressive cyst expansion distorts the kidney architecture and ultimately leads to ESKD in a large proportion of patients4. With the recent approval of Tolvaptan as the first disease-modifer drug for ADPKD5,6, identifying high-risk patients who may benefit from this treatment is a clinical priority7,8. Te Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease has shown that total kidney volume (TKV) expands quasi-exponentially during adult life at ~5% per year and is a sensitive marker for predicting chronic kidney disease (CKD) progression in ADPKD9.

Using age- and height-adjusted TKV determined by magnetic resonance imaging (MRI), the Mayo Clinic Imaging Classification (MCIC) provides a validated approach for CKD risk stratifcation10,11, for enrichment of high-risk patients in clinical trials11,12, and is now commonly used in clinical practice13. However, it requires visual inspection of MR images to exclude cases with atypical imaging patterns (class 2) which were present in 8.8% (52/590) of patients from the Mayo Clinic derivation cohort but excluded from subsequent analyses10. Te typical imaging (class 1) pattern for the Mayo Clinic Imaging Classification is defined as bilateral and diffuse cyst distribution, where all cysts similarly contribute to TKV. By contrast, atypical polycystic kidney disease is defined by one of the following imaging patterns: (i) unilateral, (ii) asymmetric, (iii) segmental, (iv) lopsided, or bilateral cystic disease with (v) unilateral or (vi) bilateral kidney atrophy (Table 1) 10. Patients with atypical polycystic kidney disease by imaging represent a distinct clinical population that has not been well characterized. Here, we report a systematic study to define the prevalence and clinical characteristics of patients with atypical polycystic kidneys by imaging.

Division of Nephrology, Department of Medicine, University Health Network and University of Toronto, 8N838, 585 University Avenue, Toronto, ON M5G 2N2, Canada. 2 Department of Medical Imaging, University Health Network and University of Toronto, Toronto, ON, Canada. 3 Division of Nephrology, Department of Medicine, St. Joseph’s Healthcare and McMaster University, Hamilton, ON, Canada. 4 CIHR SPOR Can-SOLVE Network, Vancouver, Canada. 5 These authors contributed equally: Ioan-Andrei Iliuta, Aung Zaw Win and Matthew B. Lanktree. 6 These authors jointly supervised this work: Korosh Khalili and York Pei. *Email: york.pei@uhn.ca

Results 

Prevalence of atypical imaging patterns in patients with polycystic kidney disease. From this cohort of 543 patients who presented with a clinical diagnosis suggestive of ADPKD, 20 cases were excluded because of incomplete clinical data (n=7); non-ADPKD diagnoses (n=8) including simple cysts (n=4), peripelvic cysts (n=2), congenital anomalies of the kidney and urinary tract (n=1), and cystic disease related to a COL4A1 mutation (n=1); complex diagnoses of ADPKD with second kidney disease (n=2); and no PKD1 and PKD2 mutation results available (n=3) (Supplementary Fig. S1). Afer reviewing their MRI, we found a prevalence of atypical kidney imaging patterns in 8.8% (46/523) of the study patients (Table 1): 1 unilateral, 10 asymmetric, 9 lopsided, 1 bilateral presentation with acquired unilateral atrophy, 5 segmental sparing, and 20 mild lopsided (see Fig. 1 for illustrative examples).

Clinical characteristics of patients with atypical polycystic kidney disease by imaging. The clinical characteristics of patients with typical versus atypical kidney imaging patterns are detailed in Table 2. 

Figure 1. Illustrations of atypical imaging patterns. These include unilateral (diffuse cystic involvement of only one kidney); asymmetric (diffuse cystic involvement of one kidney with mild involvement of the contralateral kidney); lopsided (bilateral distribution of cysts with mild replacement of kidney tissue with atypical cysts where 2–5 cysts account for ≥50% of total kidney volume); bilateral presentation with acquired unilateral atrophy (diffuse cystic involvement of one kidney with contralateral acquired atrophy); segmental sparing (bilateral and diffuse distribution with sparing of one kidney pole); mild lopsided (same definition as lopsided, but with the larger cysts accounting for 15–49% of total kidney volume).

Table 2. Characteristics of the study cohort. Data expressed as number (%) or median (interquartile range). eGFR, estimated glomerular filtration rate; Ht-TKV, height-adjusted total kidney volume; NMD, no mutation detected; NT, non-truncating; PT, protein-truncating; TKV, total kidney volume. an At MRI/CT scan. bOne patient who had both a PKD1 NT and a PKD2 mutation is included here. c At last follow-up

Patients with atypical polycystic kidney disease by imaging were older (55 versus 43 years, P<0.001) with a male predominance (63.0% vs. 43.8%, P=0.01); they were less likely to have a family history of ADPKD (26.1% vs. 74.6%, P<0.001) or a detectable PKD1 or PKD2 mutation (9.2% vs. 80.4%, P<0.001; Fig. 2a). Despite being more than 10 years older on average, patients with atypical kidney imaging patterns did not have a significantly different eGFR compared to those with typical kidney imaging patterns (median [IQR]: 82.0 [68.8–98.5] vs. 79.0 [49.0–101.0] mL/min/1.73 m2; P=0.3), suggesting milder CKD in the former group. Consistent with this notion, patients with atypical kidney imaging patterns showed excellent kidney survival as defined by the absence of CKD stage 3 or stage 5 (Fig. 3; P<0.001 by the log-rank test).

Image analyses of atypical polycystic kidney disease. 

Of the 46 patients with atypical polycystic kidney disease (see Supplementary Tables S1 and S2), 45 (1 unilateral disease, 10 asymmetric disease, 29 lopsided diseases, and 5 polycystic kidney disease with segmental sparing) displayed imaging patterns associated with an apparent sparing of cystic disease in one or more parts of the kidneys, which is highly unusual in patients older than 40 years of age. Notably, only 20% (9/45) of these patients had a detectable PKD1 (n=3 for non-truncating and n=1 for truncating) or PKD2 (n=5) mutation. Only one patient in this cohort displayed the pattern of acquired unilateral atrophy, without an identifiable PKD1 or PKD2 mutation.

Failure to exclude patients with atypical kidney imaging patterns can lead to erroneous CKD risk prediction by the Mayo Clinic Imaging Classification. If unrecognized, 41.3% (19/46) of our patients with atypical kidney imaging patterns would have been misclassified as being at high risk for progression to ESKD (i.e., Mayo Clinic Imaging Class 1C-1E; see Fig. 2b).

Signifcant variability in cystic liver disease severity was observed in patients with atypical polycystic kidney disease by imaging: 29 (63.0%) had fewer than two liver cysts, 11 (23.9%) had between two and ten cysts, and 6 (13.0%) had more than ten cysts. Mild liver disease (≤10 cysts) was more frequent in patients with atypical imaging patterns compared to patients with typical imaging patterns (87.0% versus 46.1%, P<0.001).

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