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Background and Objectives: Total kidney volume is a validated prognostic biomarker for autosomal dominant polycystic kidney disease. Total kidney volume by magnetic resonance imaging (MRI) and manual segmentation is considered the "reference standard," but it is time consuming and not readily accessible. By contrast, three-dimensional (3D) ultrasound provides a promising technology for total kidney volume measurements with unknown potential. Here, we report a comparative study of total kidney volume measurements by 3D ultrasound versus the conventional methods by ultrasound ellipsoid and MRI ellipsoid., Design, Setting, Participants, & Measurements: This single-center prospective study included 142 patients who completed a standardized 3D ultrasound and MRI. Total kidney volumes by 3D ultrasound and ultrasound ellipsoid were compared with those by MRI. We assessed the agreement of total kidney volume measurements by Bland-Altman plots and misclassification of the Mayo Clinic imaging classes between the different imaging methods, and we assessed prediction of Mayo Clinic imaging classes 1C-1E by average ultrasound kidney length >16.5 cm., Results: Compared with MRI manual segmentation, MRI ellipsoid, 3D ultrasound, and ultrasound ellipsoid underestimated total kidney volume (mean difference: -3%, -9%, and -11%, respectively), with Mayo Clinic imaging classes misclassified in 11%, 21%, and 22% of patients, respectively; most misclassified cases by MRI ellipsoid (11 of 16), 3D ultrasound (23 of 30), and ultrasound ellipsoid (26 of 31) were placed into a lower Mayo Clinic imaging class. Predictions of the high-risk Mayo Clinic imaging classes (1C-1E) by MRI ellipsoid, 3D ultrasound, and ultrasound ellipsoid all yielded high positive predictive value (96%, 95%, and 98%, respectively) and specificity (96%, 96%, and 99%, respectively). However, both negative predictive value (90%, 88%, and 95%, respectively) and sensitivity (88%, 85%, and 94%, respectively) were lower for 3D ultrasound and ultrasound ellipsoid compared with MRI ellipsoid. An average ultrasound kidney length >16.5 cm was highly predictive of Mayo Clinic imaging classes 1C-1E only in patients aged ≤45 years., Conclusions: Total kidney volume measurements in autosomal dominant polycystic kidney disease by 3D ultrasound and ultrasound ellipsoid displayed similar bias and variability and are less accurate than MRI ellipsoid. Prediction of high-risk Mayo Clinic imaging classes (1C-1E) by all three methods provides high positive predictive value, but ultrasound ellipsoid is simpler to use and more readily available., (Copyright © 2022 by the American Society of Nephrology.)

Background and Objectives: A preference-based health utility score (PROPr) can be calculated using Patient-Reported Outcomes Measurement Information System domain scores. We assessed the construct validity of PROPr among patients treated with KRT (hemodialysis or kidney transplant)., Design, Setting, Participants, & Measurements: We performed a secondary analysis of data collected in multicenter, cross-sectional studies of adults treated with KRT, recruited between April 2016 to March 2020 in Toronto, Canada. All participants provided informed consent. The outcome was the PROPr score. Coadministered outcome variables included the Short-Form Six-Domain (SF-6D) and EuroQol Five-Domain Five-Level (EQ-5D-5L) scores. Socioeconomic and clinical variables included age, sex, diabetes, eGFR, serum albumin, hemoglobin, KRT, and Charlson Comorbidity Index. Construct validity was assessed through correlations between PROPr and SF-6D or EQ-5D-5L, and associations between PROPr and other exposure variables. Health-condition impact estimates (coefficients for health conditions compared with a referent category, e.g. , dialysis versus kidney transplant) were calculated using multivariable linear regression., Results: The mean (SD) age of the 524 participants was 57 (17) years, 58% were male, and 45% were White. Median (interquartile range) score was 0.39 (0.24-0.58) for PROPr, 0.69 (0.58-0.86) for SF-6D, and 0.85 (0.70-0.91) for EQ-5D-5L. Large correlations were observed between PROPr versus SF-6D (0.79; 95% confidence interval [95% CI], 0.76 to 0.82) and EQ-5D-5L (0.71; 95% CI, 0.66 to 0.75). Both PROPr and the other utility indices demonstrated health-condition impact in the expected direction. For example, the estimate for PROPr was -0.17 (95% CI, -0.13 to -0.21) for dialysis (versus kidney transplant), -0.05 (95% CI, -0.11 to 0.01; P =0.08) for kidney transplant recipients with an eGFR of <45 versus ≥45 ml/min per 1.73 m 2 , and -0.28 (95% CI, -0.22 to -0.33) for moderate/severe versus no/mild depressive symptoms., Conclusions: Our results support the validity of PROPr among patients treated with KRT., (Copyright © 2021 by the American Society of Nephrology.)

Autosomal dominant polycystic kidney disease is the most common monogenic cause of ESKD. Genetic studies from patients and animal models have informed disease pathobiology and strongly support a "threshold model" in which cyst formation is triggered by reduced functional polycystin dosage below a critical threshold within individual tubular epithelial cells due to ( 1 ) germline and somatic PKD1 and/or PKD2 mutations, ( 2 ) mutations of genes ( e.g. , SEC63 , SEC61B , GANAB , PRKCSH , DNAJB11 , ALG8 , and ALG9 ) in the endoplasmic reticulum protein biosynthetic pathway, or ( 3 ) somatic mosaicism. Genetic testing has the potential to provide diagnostic and prognostic information in cystic kidney disease. However, mutation screening of PKD1 is challenging due to its large size and complexity, making it both costly and labor intensive. Moreover, conventional Sanger sequencing-based genetic testing is currently limited in elucidating the causes of atypical polycystic kidney disease, such as within-family disease discordance, atypical kidney imaging patterns, and discordant disease severity between total kidney volume and rate of eGFR decline. In addition, environmental factors, genetic modifiers, and somatic mosaicism also contribute to disease variability, further limiting prognostication by mutation class in individual patients. Recent innovations in next-generation sequencing are poised to transform and extend molecular diagnostics at reasonable costs. By comprehensive screening of multiple cystic disease and modifier genes, targeted gene panel, whole-exome, or whole-genome sequencing is expected to improve both diagnostic and prognostic accuracy to advance personalized medicine in autosomal dominant polycystic kidney disease., (Copyright © 2021 by the American Society of Nephrology.)

Background and Objectives: Progression of autosomal dominant polycystic kidney disease (ADPKD) is highly variable. On average, protein-truncating PKD1 mutations are associated with the most severe kidney disease among all mutation classes. Here, we report that patients with protein-truncating PKD1 mutations may also have mild kidney disease, a finding not previously well recognized., Design, Setting, Participants, & Measurements: From the extended Toronto Genetic Epidemiologic Study of Polycystic Kidney Disease, 487 patients had PKD1 and PKD2 sequencing and typical ADPKD imaging patterns by magnetic resonance imaging or computed tomography. Mayo Clinic Imaging Classification on the basis of age- and height-adjusted total kidney volume was used to assess their cystic disease severity; classes 1A or 1B were used as a proxy to define mild disease. Multivariable linear regression was performed to test the effects of age, sex, and mutation classes on log-transformed height-adjusted total kidney volume and eGFR., Results: Among 174 study patients with typical imaging patterns and protein-truncating PKD1 mutations, 32 (18%) were found to have mild disease on the basis of imaging results ( i.e ., Mayo Clinic Imaging class 1A-1B), with their mutations spanning the entire gene. By multivariable analyses of age, sex, and mutation class, they displayed mild disease similar to patients with PKD2 mutations and Mayo Clinic Imaging class 1A-1B. Most of these mildly affected patients with protein-truncating PKD1 mutations reported a positive family history of ADPKD in preceding generations and displayed significant intrafamilial disease variability., Conclusions: Despite having the most severe mutation class, 18% of patients with protein-truncating PKD1 mutations had mild disease on the basis of clinical and imaging assessment., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021&#95;02&#95;18&#95;CJN11100720&#95;final.mp3., (Copyright © 2021 by the American Society of Nephrology.)

Background: Vascular calcification is common among patients undergoing dialysis and is associated with mortality. Factors such as osteoprotegerin (OPG), osteopontin (OPN), bone morphogenic protein-7 (BMP-7), and fetuin-A are involved in vascular calcification., Design, Setting, Participants, & Measurements: OPG, OPN, BMP-7, and fetuin-A were measured in blood samples from 602 incident dialysis patients recruited from United States dialysis centers between 1995 and 1998 as part of the Choices for Healthy Outcomes In Caring for ESRD Study. Their association with all-cause and cardiovascular mortality were assessed using Cox proportional hazards models adjusted for demographic characteristics, comorbidity, serum phosphate, and calcium. An interaction with diabetes was tested because of its known association with vascular calcification. Predictive accuracy of selected biomarkers was explored by C-statistics in nested models with training and validation subcohorts., Results: Higher OPG and lower fetuin-A levels were associated with higher mortality over up to 13 years of follow-up (median, 3.4 years). The adjusted hazard ratios (HR) for highest versus lowest tertile were 1.49 (95% confidence interval [95% CI], 1.08 to 2.06) for OPG and 0.69 (95% CI, 0.52 to 0.92) for fetuin-A. In stratified models, the highest tertile of OPG was associated with higher mortality among patients without diabetes (HR, 2.42; 95% CI, 1.35 to 4.34), but not patients with diabetes (HR, 1.26; 95% CI, 0.82 to 1.93; P for interaction=0.001). In terms of cardiovascular mortality, higher fetuin-A was associated with lower risk (HR, 0.85 per 0.1 g/L: 95% CI, 0.75 to 0.96). In patients without diabetes, higher OPG was associated with greater risk (HR for highest versus lowest tertile, 2.91; 95% CI, 1.06 to 7.99), but not in patients with diabetes or overall. OPN and BMP-7 were not independently associated with outcomes overall. The addition of OPG and fetuin-A did not significantly improve predictive accuracy of mortality., Conclusions: OPG and fetuin-A may be risk factors for all-cause and cardiovascular mortality in patients undergoing dialysis, but do not improve risk prediction.

Background and Objectives: Mutation-based molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) is complicated by locus and allelic heterogeneity, large multi-exon gene structure and duplication in PKD1, and a high level of unclassified variants. Comprehensive screening of PKD1 and PKD2 by two recent studies have shown that atypical splice mutations account for 3.5% to 5% of ADPKD. We evaluated the role of bioinformatic prediction of atypical splice mutations and determined the pathogenicity of an atypical PKD2 splice variant from a multiplex ADPKD (TOR101) family., Design, Setting, Participants, & Measurements: Using PubMed, we identified 17 atypical PKD1 and PKD2 splice mutations. We found that bioinformatics analysis was often useful for evaluating the pathogenicity of these mutations, although RT-PCR is needed to provide the definitive proof., Results: Sequencing of both PKD1 and PKD2 in an affected subject of TOR101 failed to identify a definite mutation, but revealed several UCVs, including an atypical PKD2 splice variant. Linkage analysis with microsatellite markers indicated that TOR101 was PKD2-linked and IVS8 + 5G-->A was shown to cosegregate only with affected subjects. RT-PCR of leukocyte mRNA from an affected subject using primers from exons 7 and 9 revealed six splice variants that resulted from activation of different combinations of donor and acceptor cryptic splice sites, all terminating with premature stop codons., Conclusions: The data provide strong evidence that IVS8 + 5G-->A is a pathogenic mutation for PKD2. This case highlights the importance of functional analysis of UCVs.

Recessive NPHS2 (podocin) mutations account for up to approximately 30% of steroid-resistant idiopathic FSGS in children and are associated with a reduced risk for disease recurrence after renal transplantation. R229Q, a missense variant that is present in 3.6% of the white population, has been implicated as a common disease-causing mutation. Given these clinical implications, we examined the role of NPHS2 mutations in a cohort of patients with adult-onset FSGS. We used denaturing HPLC to screen for heterozygous and homozygous gene variants in PCR-amplified DNA fragments that contained all exons and splice junctions of NPHS2. Bidirectional sequencing was performed to define all of the gene variants detected. With the use of the denaturing HPLC in a single-blind pilot study, 40 of 43 known NPHS2 mutations were detected from 22 pediatric patients with FSGS to establish a test sensitivity of 93%. This screen then was applied to 87 adult patients with idiopathic FSGS (15 steroid-sensitive, 63 steroid-resistant, and nine familial cases). In this latter cohort, compound heterozygous mutations were detected only in one patient with steroid-sensitive FSGS (R229Q and Q285fsX302) and no homozygous mutations. Overall, R229Q accounted for eight (80%) of ten of the putative mutant alleles that were detected in the study cohort. Contrary to the pediatric experience, recessive NPHS2 mutations are rare in this study population, suggesting that the pathogenesis of FSGS in adults may differ from that in children. These data do not support R229Q as a disease-causing mutation for steroid-resistant FSGS.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common Mendelian disorder of the kidney and affects all racial groups worldwide. It is characterized by focal development of renal and extrarenal cysts in an age-dependent manner. Typically, only a few renal cysts are detected in most affected individuals before 30 yr of age. However, by the fifth decade of life, hundreds to thousands of renal cysts will be found in the majority of patients. ADPKD is genetically heterogeneous. Mutations of two genes, PKD1 and PKD2, account for approximately 85 and 15% of cases, respectively. Although the clinical manifestations of these two genotypes overlap completely, patients with PKD1 have much more severe renal disease compared with those with PKD2, as evidenced by their ESRD occurring approximately 15 yr earlier. Renal ultrasonography commonly is used for the assessment of ADPKD, and age-dependent ultrasound diagnostic criteria with high sensitivity and specificity have been established for individuals who are born with 50% risk for PKD1. Although these diagnostic criteria are used widely for genetic counseling and for the evaluation of at-risk individuals as living-related kidney donors to their affected relatives, their application to individuals who are at risk for PKD2 or have undefined genotype needs to be refined further. Molecular genetic testing is available for ADPKD and may be useful for evaluation of at-risk individuals with equivocal imaging results, younger at-risk individuals as a living-related kidney donor, and individuals with atypical or de novo renal cystic disease.