Publications by authors named "Peter C Harris"

217 Publications

Haploinsufficiency Ameliorates Renal Cysts and Cilia Abnormality in Adult Zebrafish Mutants.

J Am Soc Nephrol 2021 Feb 11. Epub 2021 Feb 11.

Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota

Background: Although zebrafish embryos have been used to study ciliogenesis and model polycystic kidney disease (PKD), adult zebrafish remain unexplored.

Methods: Transcription activator-like effector nucleases (TALEN) technology was used to generate mutant for , the homolog of the mammalian causative gene for Meckel syndrome type 3 (MKS3). Classic 2D and optical-clearing 3D imaging of an isolated adult zebrafish kidney were used to examine cystic and ciliary phenotypes. A hypomorphic strain or rapamycin was used to inhibit mTOR activity.

Results: Adult zebrafish developed progressive mesonephric cysts that share conserved features of mammalian cystogenesis, including a switch of cyst origin with age and an increase in proliferation of cyst-lining epithelial cells. The mutants had shorter and fewer distal single cilia and greater numbers of multiciliated cells (MCCs). Absence of a single cilium preceded cystogenesis, and expansion of MCCs occurred after pronephric cyst formation and was inversely correlated with the severity of renal cysts in young adult zebrafish, suggesting a primary defect and an adaptive action, respectively. Finally, the mutants exhibited hyperactive mTOR signaling. mTOR inhibition ameliorated renal cysts in both the embryonic and adult zebrafish models; however, it only rescued ciliary abnormalities in the adult mutants.

Conclusions: Adult zebrafish mutants offer a new vertebrate model for renal cystic diseases, in which cilia morphology can be analyzed at a single-nephron resolution and mTOR inhibition proves to be a candidate therapeutic strategy.
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http://dx.doi.org/10.1681/ASN.2020070991DOI Listing
February 2021

Up-regulation of DNA Damage Response Signaling in Autosomal Dominant Polycystic Kidney Disease.

Am J Pathol 2021 Feb 4. Epub 2021 Feb 4.

Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney NSW, Australia; Department of Renal Medicine, Westmead Hospital, Western Sydney Local Health District, Sydney NSW, Australia. Electronic address:

DNA damage and alterations in DNA Damage Response (DDR) signaling could be one of the molecular mechanisms mediating focal kidney cyst formation in autosomal dominant polycystic kidney disease (ADPKD). The aim of this study was to test the hypothesis that markers of DNA damage and DDR signaling are increased in human and experimental ADPKD. In the human ADPKD transcriptome, the number of upregulated DDR-related genes was increased by 16.6-fold compared to normal kidney, and by 2.5-fold in cystic compared to minimally cystic tissue (P<0.0001). In end-stage human ADPKD tissue, gamma (γ)-H2AX, phosphorylated Ataxia Telangiectasia and Rad3-related (p-ATR) and AT Mutated (p-ATM) localized to cystic kidney epithelial cells. In vitro, p-ATR and p-ATM were also constitutively increased in human ADPKD tubular cells (WT 9-7, 9-12) compared to control (HK-2). Additionally, extrinsic oxidative DNA damage by HO augmented γ-H2AX and cell survival in human ADPKD cells, and exacerbated cyst growth in the 3D MDCK cyst model. In contrast, DDR-related gene expression was only transiently increased on postnatal day 0 in Pkd1 mice, and not altered at later timepoints up to 12 months of age. In conclusion, DDR signaling is dysregulated in human ADPKD and during the early phases of murine ADPKD. The constitutive expression of the DDR pathway in ADPKD may promote survival of PKD1-mutated cells and contribute to kidney cyst growth.
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http://dx.doi.org/10.1016/j.ajpath.2021.01.011DOI Listing
February 2021

Clinical characterization of primary hyperoxaluria type 3 in comparison to types 1 and 2: a retrospective cohort study.

Nephrol Dial Transplant 2021 Feb 5. Epub 2021 Feb 5.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.

Background: Primary hyperoxaluria type 3 (PH3) is caused by mutations in the HOGA1 gene. PH3 patients often present with recurrent urinary stone disease (USD) in first decade of life, but prior reports suggested PH3 may have a milder phenotype in adults. The current study characterized clinical manifestations of PH3 across the decades of life in comparison to PH1 and PH2.

Methods: Clinical information was obtained from the Rare Kidney Stone Consortium Primary Hyperoxaluria Registry (PH1 n = 384; PH2 n = 51; PH3 n = 62).

Results: PH3 patients presented with symptoms at a median 2.7 yrs old compared to PH1 (4.9 yrs) and PH2 (5.7 yrs) (p = 0.14). Nephrocalcinosis was present at diagnosis in 4 (7%) PH3 patients while 55 (89%) had stones. Median urine oxalate excretion was lowest in PH3 patients compared to PH1 and PH2 (1.1 vs 1.6 and 1.5 mmol/day/1.73m2, respectively, p < 0.001) while urine calcium was highest in PH3 (112 vs 51 and 98 mg/day/1.73m2 in PH1 and PH2, respectively, p < 0.001). Stone events per decade of life were similar across the age span and the 3 PH types. At 40 years of age, 97% of PH3 patients had not progressed to ESKD compared to 36% PH1 and 66% PH2 patients.

Conclusions: Patients with all forms of PH experience lifelong stone events often beginning in childhood. Kidney failure is common in PH1 but rare in PH3. Longer term follow up of larger cohorts will be important for a more complete understanding of the PH3 phenotype.
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http://dx.doi.org/10.1093/ndt/gfab027DOI Listing
February 2021

The genetic landscape of polycystic kidney disease in Ireland.

Eur J Hum Genet 2021 Jan 16. Epub 2021 Jan 16.

School of Pharmacy and Biomolecular Science, Royal College of Surgeons in Ireland, Dublin, Ireland.

Polycystic kidney diseases (PKDs) comprise the most common Mendelian forms of renal disease. It is characterised by the development of fluid-filled renal cysts, causing progressive loss of kidney function, culminating in the need for renal replacement therapy or kidney transplant. Ireland represents a valuable region for the genetic study of PKD, as family sizes are traditionally large and the population relatively homogenous. Studying a cohort of 169 patients, we describe the genetic landscape of PKD in Ireland for the first time, compare the clinical features of patients with and without a molecular diagnosis and correlate disease severity with autosomal dominant pathogenic variant type. Using a combination of molecular genetic tools, including targeted next-generation sequencing, we report diagnostic rates of 71-83% in Irish PKD patients, depending on which variant classification guidelines are used (ACMG or Mayo clinic respectively). We have catalogued a spectrum of Irish autosomal dominant PKD pathogenic variants including 36 novel variants. We illustrate how apparently unrelated individuals carrying the same autosomal dominant pathogenic variant are highly likely to have inherited that variant from a common ancestor. We highlight issues surrounding the implementation of the ACMG guidelines for variant pathogenicity interpretation in PKD, which have important implications for clinical genetics.
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http://dx.doi.org/10.1038/s41431-020-00806-5DOI Listing
January 2021

Genomic diagnostics in polycystic kidney disease: an assessment of real-world use of whole-genome sequencing.

Eur J Hum Genet 2021 Jan 12. Epub 2021 Jan 12.

Division of Genomics and Epigenetics, Garvan Institute of Medical Research, Sydney, NSW, Australia.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is common, with a prevalence of 1/1000 and predominantly caused by disease-causing variants in PKD1 or PKD2. Clinical diagnosis is usually by age-dependent imaging criteria, which is challenging in patients with atypical clinical features, without family history, or younger age. However, there is increasing need for definitive diagnosis of ADPKD with new treatments available. Sequencing is complicated by six pseudogenes that share 97% homology to PKD1 and by recently identified phenocopy genes. Whole-genome sequencing can definitively diagnose ADPKD, but requires validation for clinical use. We initially performed a validation study, in which 42 ADPKD patients underwent sequencing of PKD1 and PKD2 by both whole-genome and Sanger sequencing, using a blinded, cross-over method. Whole-genome sequencing identified all PKD1 and PKD2 germline pathogenic variants in the validation study (sensitivity and specificity 100%). Two mosaic variants outside pipeline thresholds were not detected. We then examined the first 144 samples referred to a clinically-accredited diagnostic laboratory for clinical whole-genome sequencing, with targeted-analysis to a polycystic kidney disease gene-panel. In this unselected, diagnostic cohort (71 males :73 females), the diagnostic rate was 70%, including a diagnostic rate of 81% in patients with typical ADPKD (98% with PKD1/PKD2 variants) and 60% in those with atypical features (56% PKD1/PKD2; 44% PKHD1/HNF1B/GANAB/ DNAJB11/PRKCSH/TSC2). Most patients with atypical disease did not have clinical features that predicted likelihood of a genetic diagnosis. These results suggest clinicians should consider diagnostic genomics as part of their assessment in polycystic kidney disease, particularly in atypical disease.
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http://dx.doi.org/10.1038/s41431-020-00796-4DOI Listing
January 2021

CYP24A1 deficiency causing persistent hypercalciuria in a stone former.

J Nephrol 2021 Jan 2. Epub 2021 Jan 2.

Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN, 55905, USA.

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http://dx.doi.org/10.1007/s40620-020-00927-6DOI Listing
January 2021

Disrupting polycystin-2 EF hand Ca affinity does not alter channel function or contribute to polycystic kidney disease.

J Cell Sci 2020 Dec 24;133(24). Epub 2020 Dec 24.

Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA

Approximately 15% of autosomal dominant polycystic kidney disease (ADPKD) is caused by variants in encodes polycystin-2, which forms an ion channel in primary cilia and endoplasmic reticulum (ER) membranes of renal collecting duct cells. Elevated internal Ca modulates polycystin-2 voltage-dependent gating and subsequent desensitization - two biophysical regulatory mechanisms that control its function at physiological membrane potentials. Here, we refute the hypothesis that Ca occupancy of the polycystin-2 intracellular EF hand is responsible for these forms of channel regulation, and, if disrupted, results in ADPKD. We identify and introduce mutations that attenuate Ca-EF hand affinity but find channel function is unaltered in the primary cilia and ER membranes. We generated two new mouse strains that harbor distinct mutations that abolish Ca-EF hand association but do not result in a PKD phenotype. Our findings suggest that additional Ca-binding sites within polycystin-2 or Ca-dependent modifiers are responsible for regulating channel activity.
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http://dx.doi.org/10.1242/jcs.255562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774883PMC
December 2020

Biallelic inheritance of hypomorphic PKD1 variants is highly prevalent in very early onset polycystic kidney disease.

Genet Med 2020 Nov 10. Epub 2020 Nov 10.

Kidney Genetics Group, Academic Nephrology Unit, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, Sheffield, UK.

Purpose: To investigate the prevalence of biallelic PKD1 and PKD2 variants underlying very early onset (VEO) polycystic kidney disease (PKD) in a large international pediatric cohort referred for clinical indications over a 10-year period (2010-2020).

Methods: All samples were tested by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) of PKD1 and PKD2 genes and/or a next-generation sequencing panel of 15 additional cystic genes including PKHD1 and HNF1B. Two patients underwent exome or genome sequencing.

Results: Likely causative PKD1 or PKD2 variants were detected in 30 infants with PKD-VEO, 16 of whom presented in utero. Twenty-one of 30 (70%) had two variants with biallelic in trans inheritance confirmed in 16/21, 1 infant had biallelic PKD2 variants, and 2 infants had digenic PKD1/PKD2 variants. There was no known family history of ADPKD in 13 families (43%) and a de novo pathogenic variant was confirmed in 6 families (23%).

Conclusion: We report a high prevalence of hypomorphic PKD1 variants and likely biallelic disease in infants presenting with PKD-VEO with major implications for reproductive counseling. The diagnostic interpretation and reporting of these variants however remains challenging using current American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) and Association of Clinical Genetic Science (ACGS) variant classification guidelines in PKD-VEO and other diseases affected by similar variants with incomplete penetrance.
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http://dx.doi.org/10.1038/s41436-020-01026-4DOI Listing
November 2020

Epidemiology of autosomal-dominant polycystic liver disease in Olmsted county.

JHEP Rep 2020 Dec 4;2(6):100166. Epub 2020 Aug 4.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.

Background & Aims: Isolated autosomal-dominant polycystic liver disease (ADPLD) is generally considered a rare disease. However, the frequency of truncating mutations to ADPLD genes in large, population sequencing databases is 1:496. With the increasing use of abdominal imaging, incidental detection of hepatic cysts and ADPLD has become more frequent. The present study was performed to ascertain the incidence and point prevalence of ADPLD in Olmsted County, MN, USA, and how these are impacted by the increasing utilisation of abdominal imaging.

Methods: The Rochester Epidemiology Project and radiology databases of Mayo Clinic and Olmsted Medical Center were searched to identify all subjects meeting diagnostic criteria for definite, likely, or possible ADPLD. Annual incidence rates were calculated using incident cases during 1980-2016 as numerator, and age- and sex-specific estimates of the population of Olmsted County as denominator. Point prevalence was calculated using prevalence cases as numerator, and age- and sex-specific estimates of the population of Olmsted County on 1 January 2010 as denominator.

Results: The incidence rate and point prevalence of combined definite and likely ADPLD were 1.01 per 100,000 person-years and 9.5 per 100,000 population, respectively. Only 15 of 35 definite and likely incident ADPLD cases had received a diagnostic code, and only 8 had clinically significant hepatomegaly. The incidence rates were much higher when adding possible cases, mainly identified through radiology databases, particularly in recent years and in older patients because of the increased utilisation of imaging studies.

Conclusions: Clinically significant isolated ADPLD is a rare disease with a prevalence <1:10,000 population. The overall prevalence of ADPLD, however, to a large extent not clinically significant, is likely much higher and closer to the reported genetic prevalence.

Lay Summary: Isolated autosomal-dominant polycystic liver disease (ADPLD) is generally considered a rare disease. However, we demonstrate that it is a relatively common disease, which is rarely (<1:10,000 population) clinically significant.
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http://dx.doi.org/10.1016/j.jhepr.2020.100166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593615PMC
December 2020

Cross-talk between CDK4/6 and SMYD2 regulates gene transcription, tubulin methylation, and ciliogenesis.

Sci Adv 2020 Oct 30;6(44). Epub 2020 Oct 30.

Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.

Dysregulation of cyclin-dependent kinases 4 and 6 (CDK4/6) by unknown mechanisms is highly prevalent in human disease. In this study, we identify direct cross-talk between CDK4/6 and the epigenome via its previously unidentified substrate, SMYD2, a histone/lysine methyltransferase. CDK4/6 positively regulates the phosphorylation and enzymatic activity of SMYD2, while SMYD2 also positively regulates the expression of CDK4/6. We also identify SMYD2 as an α-tubulin methyltransferase, thus connecting CDK4/6-SMYD2 signaling to microtubule dynamics. In addition, depletion or inhibition of CDK4/6 and SMYD2 resulted in increased cilia assembly by affecting (i) microtubule stability and (ii) the expression of IFT20, further connecting CDK4/6-SMYD2 to ciliogenesis. In clinical settings such as breast cancer and autosomal dominant polycystic kidney disease (ADPKD), targeting the up-regulated CDK4/6 and SMYD2 with inhibitors results in restoration of the primary cilium in tumor and cystic cells, which may normalize cilia-mediated extracellular signals that regulate growth, development, and cellular homeostasis.
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http://dx.doi.org/10.1126/sciadv.abb3154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608814PMC
October 2020

Impaired Hedgehog-Gli1 Pathway Activity Underlies the Vascular Phenotype of Polycystic Kidney Disease.

Hypertension 2020 Dec 5;76(6):1889-1897. Epub 2020 Oct 5.

From the Department of Cardiovascular Medicine (F.F., K.M.P., K.Q., D.D., M.O., M.P., M.G.R.-P.), Mayo Clinic, Rochester, MN.

Polycystic kidney disease (PKD) has been linked to abnormal structure/function of ciliary proteins, leading to renal dysfunction. Recently, attention has been focused in the significant vascular abnormalities associated with PKD, but the mechanisms underlying this phenomenon remain elusive. Here, we seek to define the molecular events regulating the angiogenic imbalance observed in PKD. Using micro computed tomography (n=7) and protein expression analysis (n=5), we assessed the vascular density and the angiogenic profile of noncystic organs in a well-established PKD rat model (Polycystic Kidney-PCK rat). Heart and lungs of PCK rats have reduced vascular density and decreased expression of angiogenic factors compared with wild type. Similarly, PCK-vascular smooth muscle cells (VSMCs; n=4) exhibited lower levels of vascular markers. Then, using small interfering RNA (n=4), we determined the role of the ciliary protein fibrocystin in wild type-VSMCs, a critical component/regulator of vascular structure and function. Reduction of fibrocystin in wild type-VSMCs (n=4) led to an abnormal angiogenic potential similar to that observed in PCK-VSMCs. Furthermore, we investigated the involvement of the hedgehog signaling, a pathway closely linked to the primary cilium and associated with vascular development, in PKD. Mechanistically, we demonstrated that impairment of the hedgehog signaling mediates, in part, this abnormal angiogenic phenotype. Lastly, overexpression of Gli1 in PCK-VSMCs (n=4) restored the expression levels of proangiogenic molecules. Our data support a critical role of fibrocystin in the abnormal vascular phenotype of PKD and indicate that a dysregulation of hedgehog may be responsible, at least in part, for these vascular deficiencies.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666088PMC
December 2020

Pansomatostatin Agonist Pasireotide Long-Acting Release for Patients with Autosomal Dominant Polycystic Kidney or Liver Disease with Severe Liver Involvement: A Randomized Clinical Trial.

Clin J Am Soc Nephrol 2020 Sep 25;15(9):1267-1278. Epub 2020 Aug 25.

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota.

Background And Objectives: We assessed safety and efficacy of another somatostatin receptor analog, pasireotide long-acting release, in severe polycystic liver disease and autosomal dominant polycystic kidney disease. Pasireotide long-acting release, with its broader binding profile and higher affinity to known somatostatin receptors, has potential for greater efficacy.

Design, Setting, Participants, & Measurements: Individuals with severe polycystic liver disease were assigned in a 2:1 ratio in a 1-year, double-blind, randomized trial to receive pasireotide long-acting release or placebo. Primary outcome was change in total liver volume; secondary outcomes were change in total kidney volume, eGFR, and quality of life.

Results: Of 48 subjects randomized, 41 completed total liver volume measurements (=29 pasireotide long-acting release and =12 placebo). From baseline, there were -99±189 ml/m absolute and -3%±7% change in annualized change in height-adjusted total liver volume (from 2582±1381 to 2479±1317 ml/m) in the pasireotide long-acting release group compared with 136±117 ml/m absolute and 6%±7% increase (from 2387±759 to 2533±770 ml/m) in placebo (<0.001 for both). Total kidney volumes decreased by -12±34 ml/m and -1%±4% in pasireotide long-acting release compared with 21±21 ml/m and 4%±5% increase in the placebo group (=0.05 for both). Changes in eGFR were similar between groups. Among the =48 randomized, adverse events included hyperglycemia (26 of 33 [79%] in pasireotide long-acting release versus four of 15 [27%] in the placebo group; <0.001), and among the 47 without diabetes at baseline, 19 of 32 (59%) in the pasireotide long-acting release group versus one of 15 (7%) in the placebo group developed diabetes (=0.001).

Conclusions: Another somatostatin analog, pasireotide long-acting release, slowed progressive increase in both total liver volume/total kidney volume growth rates without affecting GFR decline. Participants experienced higher frequency of adverse events (hyperglycemia and diabetes).

Clinical Trial Registry Name And Registration Number: Pasireotide LAR in Severe Polycystic Liver Disease, NCT01670110 PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_08_28_CJN13661119.mp3.
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http://dx.doi.org/10.2215/CJN.13661119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480539PMC
September 2020

RNA helicase p68 inhibits the transcription and post-transcription of in ADPKD.

Theranostics 2020 9;10(18):8281-8297. Epub 2020 Jul 9.

Department of Internal Medicine and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905.

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations of the and genes. Dysregulation of the expression of PKD genes, the abnormal activation of PKD associated signaling pathways, and the expression and maturation of miRNAs regulates cyst progression. However, the upstream factors regulating these abnormal processes in ADPKD remain elusive. To investigate the roles of an RNA helicase, p68, in ADPKD, we performed Western blot and qRT-PCR analysis, immunostaining and ChIP assay in cystic renal epithelium cells and tissues. We found that p68 was upregulated in cystic renal epithelial cells and tissues. p68 represses gene expression via transcriptional and posttranscriptional mechanisms in renal epithelial cells, in that 1) p68 binds to the promoter of the gene together with p53 to repress transcription; and 2) p68 promotes the expression and maturation of miR-17, miR-200c and miR-182 and via these miRNAs, post-transcriptionally regulates the expression of mRNA. Drosha is involved in this process by forming a complex with p68. p68 also regulates the phosphorylation and activation of PKD proliferation associated signaling and the expression of fibrotic markers in mutant renal epithelial cells. Silence of p68 delays cyst formation in collecting duct cell mediated 3D cultures. In addition, the expression of p68 is induced by HO-dependent oxidative stress and DNA damage which causes downregulation of transcription in cystic renal epithelial cells and tissues. p68 plays a critical role in negatively regulating the expression of the gene along with positively regulating the expression and maturation of miRNAs and activation of PKD associated signaling pathways to cause renal cyst progression and fibrosis in ADPKD.
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http://dx.doi.org/10.7150/thno.47315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381742PMC
July 2020

The value of genotypic and imaging information to predict functional and structural outcomes in ADPKD.

JCI Insight 2020 08 6;5(15). Epub 2020 Aug 6.

Division of Nephrology and Hypertension.

BACKGROUNDA treatment option for autosomal dominant polycystic kidney disease (ADPKD) has highlighted the need to identify rapidly progressive patients. Kidney size/age and genotype have predictive power for renal outcomes, but their relative and additive value, plus associated trajectories of disease progression, are not well defined.METHODSThe value of genotypic and/or kidney imaging data (Mayo Imaging Class; MIC) to predict the time to functional (end-stage kidney disease [ESKD] or decline in estimated glomerular filtration rate [eGFR]) or structural (increase in height-adjusted total kidney volume [htTKV]) outcomes were evaluated in a Mayo Clinic PKD1/PKD2 population, and eGFR and htTKV trajectories from 20-65 years of age were modeled and independently validated in similarly defined CRISP and HALT PKD patients.RESULTSBoth genotypic and imaging groups strongly predicted ESKD and eGFR endpoints, with genotype improving the imaging predictions and vice versa; a multivariate model had strong discriminatory power (C-index = 0.845). However, imaging but not genotypic groups predicted htTKV growth, although more severe genotypic and imaging groups had larger kidneys at a young age. The trajectory of eGFR decline was linear from baseline in the most severe genotypic and imaging groups, but it was curvilinear in milder groups. Imaging class trajectories differentiated htTKV growth rates; severe classes had rapid early growth and large kidneys, but growth later slowed.CONCLUSIONThe value of imaging, genotypic, and combined data to identify rapidly progressive patients was demonstrated, and reference values for clinical trials were provided. Our data indicate that differences in kidney growth rates before adulthood significantly define patients with severe disease.FUNDINGNIDDK grants: Mayo DK058816 and DK090728; CRISP DK056943, DK056956, DK056957, and DK056961; and HALT PKD DK062410, DK062408, DK062402, DK082230, DK062411, and DK062401.
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http://dx.doi.org/10.1172/jci.insight.138724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455088PMC
August 2020

Clinical spectrum, prognosis and estimated prevalence of DNAJB11-kidney disease.

Kidney Int 2020 08 23;98(2):476-487. Epub 2020 Mar 23.

Department of Nephrology, Hemodialysis and Renal Transplantation, University Hospital, Brest, France; Univ Brest, F-29200 Brest, France; National Institute for Research in Health Science (INSERM) UMR 1078, "Genetics, Genomics and Biotechnologies," Brest, France. Electronic address:

Monoallelic mutations of DNAJB11 were recently described in seven pedigrees with atypical clinical presentations of autosomal dominant polycystic kidney disease. DNAJB11 encodes one of the main cofactors of the endoplasmic reticulum chaperon BiP, a heat-shock protein required for efficient protein folding and trafficking. Here we conducted an international collaborative study to better characterize the DNAJB11-associated phenotype. Thirteen different loss-of-function variants were identified in 20 new pedigrees (54 affected individuals) by targeted next-generation sequencing, whole-exome sequencing or whole-genome sequencing. Amongst the 77 patients (27 pedigrees) now in total reported, 32 reached end stage kidney disease (range, 55-89 years, median age 75); without a significant difference between males and females. While a majority of patients presented with non-enlarged polycystic kidneys, renal cysts were inconsistently identified in patients under age 45. Vascular phenotypes, including intracranial aneurysms, dilatation of the thoracic aorta and dissection of a carotid artery were present in four pedigrees. We accessed Genomics England 100,000 genomes project data, and identified pathogenic variants of DNAJB11 in nine of 3934 probands with various kidney and urinary tract disorders. The clinical diagnosis was cystic kidney disease for eight probands and nephrocalcinosis for one proband. No additional pathogenic variants likely explaining the kidney disease were identified. Using the publicly available GnomAD database, DNAJB11 genetic prevalence was calculated at 0.85/10.000 individuals. Thus, establishing a precise diagnosis in atypical cystic or interstitial kidney disease is crucial, with important implications in terms of follow-up, genetic counseling, prognostic evaluation, therapeutic management, and for selection of living kidney donors.
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http://dx.doi.org/10.1016/j.kint.2020.02.022DOI Listing
August 2020

Pyridoxine Responsiveness in a Type 1 Primary Hyperoxaluria Patient With a Rare (Atypical) Gene Mutation.

Kidney Int Rep 2020 Jun 13;5(6):955-958. Epub 2020 Apr 13.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.

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http://dx.doi.org/10.1016/j.ekir.2020.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270974PMC
June 2020

Expanded Imaging Classification of Autosomal Dominant Polycystic Kidney Disease.

J Am Soc Nephrol 2020 07 2;31(7):1640-1651. Epub 2020 Jun 2.

Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Background: The Mayo Clinic imaging classification of autosomal dominant polycystic kidney disease (ADPKD) uses height-adjusted total kidney volume (htTKV) and age to identify patients at highest risk for disease progression. However, this classification applies only to patients with typical diffuse cystic disease (class 1). Because htTKV poorly predicts eGFR decline for the 5%-10% of patients with atypical morphology (class 2), imaging-based risk modeling remains unresolved.

Methods: Of 558 adults with ADPKD in the HALT-A study, we identified 25 patients of class 2A with prominent exophytic cysts (class 2Ae) and 43 patients of class 1 with prominent exophytic cysts; we recalculated their htTKVs to exclude exophytic cysts. Using original and recalculated htTKVs in association with imaging classification in logistic and mixed linear models, we compared predictions for developing CKD stage 3 and for eGFR trajectory.

Results: Using recalculated htTKVs increased specificity for developing CKD stage 3 in all participants from 82.6% to 84.2% after adjustment for baseline age, eGFR, BMI, sex, and race. The predicted proportion of class 2Ae patients developing CKD stage 3 using a cutoff of 0.5 for predicting case status was better calibrated to the observed value of 13.0% with recalculated htTKVs (45.5%) versus original htTKVs (63.6%). Using recalculated htTKVs reduced the mean paired difference between predicted and observed eGFR from 17.6 (using original htTKVs) to 4.0 ml/min per 1.73 m for class 2Ae, and from -1.7 (using original htTKVs) to 0.1 ml/min per 1.73 m for class 1.

Conclusions: Use of a recalculated htTKV measure that excludes prominent exophytic cysts facilitates inclusion of class 2 patients and reclassification of class 1 patients in the Mayo classification model.
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http://dx.doi.org/10.1681/ASN.2019101121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350997PMC
July 2020

Regulation of polycystin expression, maturation and trafficking.

Cell Signal 2020 08 8;72:109630. Epub 2020 Apr 8.

Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA. Electronic address:

The major autosomal dominant polycystic kidney disease (ADPKD) genes, PKD1 and PKD2, are wildly expressed at the organ and tissue level. PKD1 encodes polycystin 1 (PC1), a large membrane associated receptor-like protein that can complex with the PKD2 product, PC2. Various cellular locations have been described for both PC1, including the plasma membrane and extracellular vesicles, and PC2, especially the endoplasmic reticulum (ER), but compelling evidence indicates that the primary cilium, a sensory organelle, is the key site for the polycystin complex to prevent PKD. As with other membrane proteins, the ER biogenesis pathway is key to appropriately folding, performing quality control, and exporting fully folded PC1 to the Golgi apparatus. There is a requirement for binding with PC2 and cleavage of PC1 at the GPS for this folding and export to occur. Six different monogenic defects in this pathway lead to cystic disease development, with PC1 apparently particularly sensitive to defects in this general protein processing pathway. Trafficking of membrane proteins, and the polycystins in particular, through the Golgi to the primary cilium have been analyzed in detail, but at this time, there is no clear consensus on a ciliary targeting sequence required to export proteins to the cilium. After transitioning though the trans-Golgi network, polycystin-bearing vesicles are likely sorted to early or recycling endosomes and then transported to the ciliary base, possibly via docking to transition fibers (TF). The membrane-bound polycystin complex then undergoes facilitated trafficking through the transition zone, the diffusion barrier at the base of the cilium, before entering the cilium. Intraflagellar transport (IFT) may be involved in moving the polycystins along the cilia, but data also indicates other mechanisms. The ciliary polycystin complex can be ubiquitinated and removed from cilia by internalization at the ciliary base and may be sent back to the plasma membrane for recycling or to lysosomes for degradation. Monogenic defects in processes regulating the protein composition of cilia are associated with syndromic disorders involving many organ systems, reflecting the pleotropic role of cilia during development and for tissue maintenance. Many of these ciliopathies have renal involvement, likely because of faulty polycystin signaling from cilia. Understanding the expression, maturation and trafficking of the polycystins helps understand PKD pathogenesis and suggests opportunities for therapeutic intervention.
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http://dx.doi.org/10.1016/j.cellsig.2020.109630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269868PMC
August 2020

Oxidative Stress and Mitochondrial Abnormalities Contribute to Decreased Endothelial Nitric Oxide Synthase Expression and Renal Disease Progression in Early Experimental Polycystic Kidney Disease.

Int J Mol Sci 2020 Mar 14;21(6). Epub 2020 Mar 14.

Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

Vascular abnormalities are the most important non-cystic complications in Polycystic Kidney Disease (PKD) and contribute to renal disease progression. Endothelial dysfunction and oxidative stress are evident in patients with ADPKD, preserved renal function, and controlled hypertension. The underlying biological mechanisms remain unknown. We hypothesized that in early ADPKD, the reactive oxygen species (ROS)-producing nicotinamide adenine dinucleotide phosphate hydrogen (NAD(P)H)-oxidase complex-4 (NOX4), a major source of ROS in renal tubular epithelial cells (TECs) and endothelial cells (ECs), induces EC mitochondrial abnormalities, contributing to endothelial dysfunction, vascular abnormalities, and renal disease progression. Renal oxidative stress, mitochondrial morphology (electron microscopy), and NOX4 expression were assessed in 4- and 12-week-old PCK and Sprague-Dawley (wild-type, WT) control rats (n = 8 males and 8 females each). Endothelial function was assessed by renal expression of endothelial nitric oxide synthase (eNOS). Peritubular capillaries were counted in hematoxylin-eosin (H&E)-stained slides and correlated with the cystic index. The enlarged cystic kidneys of PCK rats exhibited significant accumulation of 8-hydroxyguanosine (8-OHdG) as early as 4 weeks of age, which became more pronounced at 12 weeks. Mitochondria of TECs lining cysts and ECs exhibited loss of cristae but remained preserved in non-cystic TECs. Renal expression of NOX4 was upregulated in TECs and ECs of PCK rats at 4 weeks of age and further increased at 12 weeks. Contrarily, eNOS immunoreactivity was lower in PCK vs. WT rats at 4 weeks and further decreased at 12 weeks. The peritubular capillary index was lower in PCK vs. WT rats at 12 weeks and correlated inversely with the cystic index. Early PKD is associated with NOX4-induced oxidative stress and mitochondrial abnormalities predominantly in ECs and TECs lining cysts. Endothelial dysfunction precedes capillary loss, and the latter correlates with worsening of renal disease. These observations position NOX4 and EC mitochondria as potential therapeutic targets in PKD.
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http://dx.doi.org/10.3390/ijms21061994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139316PMC
March 2020

Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis.

JCI Insight 2020 02 27;5(4). Epub 2020 Feb 27.

Department of Anesthesiology and Robert and Arlene Kogod Center on Aging.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of end-stage renal disease (ESRD). The treatment options for ADPKD are limited. We observed an upregulation in several IGF-1 pathway genes in the kidney of Pkd1RC/RC mice, a model of ADPKD. Pregnancy-associated plasma protein A (PAPP-A), a metalloproteinase that cleaves inhibitory IGF binding proteins (IGFBPs), increasing the local bioactivity of IGF-1, was highly induced in the kidney of ADPKD mice. PAPP-A levels were high in cystic fluid and kidneys of humans with ADPKD. Our studies further showed that PAPP-A transcription in ADPKD was mainly regulated through the cAMP/CREB/CBP/p300 pathway. Pappa deficiency effectively inhibited the development of cysts in the Pkd1RC/RC mice. The role of PAPP-A in cystic disease appears to be regulation of the IGF-1 pathway and cellular proliferation in the kidney. Finally, preclinical studies demonstrated that treatment with a monoclonal antibody that blocks the proteolytic activity of PAPP-A against IGFBP4 ameliorated ADPKD cystic disease in vivo in Pkd1RC/RC mice and ex vivo in embryonic kidneys. These data indicated that the PAPP-A/IGF-1 pathway plays an important role in the growth and expansion of cysts in ADPKD. Our findings introduce a therapeutic strategy for ADPKD that involves the inhibition of PAPP-A.
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http://dx.doi.org/10.1172/jci.insight.135700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101148PMC
February 2020

Detection and characterization of mosaicism in autosomal dominant polycystic kidney disease.

Kidney Int 2020 02 9;97(2):370-382. Epub 2019 Oct 9.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA. Electronic address:

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited, progressive nephropathy accounting for 4-10% of end stage renal disease worldwide. PKD1 and PKD2 are the most common disease loci, but even accounting for other genetic causes, about 7% of families remain unresolved. Typically, these unsolved cases have relatively mild kidney disease and often have a negative family history. Mosaicism, due to de novo mutation in the early embryo, has rarely been identified by conventional genetic analysis of ADPKD families. Here we screened for mosaicism by employing two next generation sequencing screens, specific analysis of PKD1 and PKD2 employing long-range polymerase chain reaction, or targeted capture of cystogenes. We characterized mosaicism in 20 ADPKD families; the pathogenic variant was transmitted to the next generation in five families and sporadic in 15. The mosaic pathogenic variant was newly discovered by next generation sequencing in 13 families, and these methods precisely quantified the level of mosaicism in all. All of the mosaic cases had PKD1 mutations, 14 were deletions or insertions, and 16 occurred in females. Analysis of kidney size and function showed the mosaic cases had milder disease than a control PKD1 population, but only a few had clearly asymmetric disease. Thus, in a typical ADPKD population, readily detectable mosaicism by next generation sequencing accounts for about 1% of cases, and about 10% of genetically unresolved cases with an uncertain family history. Hence, identification of mosaicism is important to fully characterize ADPKD populations and provides informed prognostic information.
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http://dx.doi.org/10.1016/j.kint.2019.08.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218796PMC
February 2020

Cl and H coupling properties and subcellular localizations of wildtype and disease-associated variants of the voltage-gated Cl/H exchanger ClC-5.

J Biol Chem 2020 02 18;295(6):1464-1473. Epub 2019 Dec 18.

Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905.

Dent disease 1 (DD1) is caused by mutations in the gene encoding a voltage-gated electrogenic nCl/H exchanger ClC-5. Using ion-selective microelectrodes and oocytes, here we studied Cl/H coupling properties of WT ClC-5 and four DD1-associated variants (S244L, R345W, Q629*, and T657S), along with trafficking and localization of ClC-5. WT ClC-5 had a 2Cl/H exchange ratio at a V of +40 mV with a [Cl] of 104 mm, but the transport direction did not reverse with a [Cl] of 5 mm, indicating that ClC-5-mediated exchange of two Cl out for one H in is not permissible. We hypothesized that ClC-5 and H-ATPase are functionally coupled during H-ATPase-mediated endosomal acidification, crucial for ClC-5 activation by depolarizing endosomes. ClC-5 transport that provides three net negative charges appeared self-inhibitory because of ClC-5's voltage-gated properties, but shunt conductance facilitated further H-ATPase-mediated endosomal acidification. Thus, an on-and-off "burst" of ClC-5 activity was crucial for preventing Cl exit from endosomes. The subcellular distribution of the ClC-5:S244L variant was comparable with that of WT ClC-5, but the variant had a much slower Cl and H transport and displayed an altered stoichiometry of 1.6:1. The ClC-5:R345W variant exhibited slightly higher Cl/H transport than ClC-5:S244L, but co-localized with early endosomes, suggesting decreased ClC-5:R345W membrane trafficking is perhaps in a fully functional form. The truncated ClC-5:Q629* variant displayed the lowest Cl/H exchange and was retained in the endoplasmic reticulum and -Golgi, but not in early endosomes, suggesting the nonsense mutation affects ClC-5 maturation and trafficking.
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http://dx.doi.org/10.1074/jbc.RA119.011366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008381PMC
February 2020

Spatiotemporal dynamics and heterogeneity of renal lymphatics in mammalian development and cystic kidney disease.

Elife 2019 12 6;8. Epub 2019 Dec 6.

Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

Heterogeneity of lymphatic vessels during embryogenesis is critical for organ-specific lymphatic function. Little is known about lymphatics in the developing kidney, despite their established roles in pathology of the mature organ. We performed three-dimensional imaging to characterize lymphatic vessel formation in the mammalian embryonic kidney at single-cell resolution. In mouse, we visually and quantitatively assessed the development of kidney lymphatic vessels, remodeling from a ring-like anastomosis under the nascent renal pelvis; a site of VEGF-C expression, to form a patent vascular plexus. We identified a heterogenous population of lymphatic endothelial cell clusters in mouse and human embryonic kidneys. Exogenous VEGF-C expanded the lymphatic population in explanted mouse embryonic kidneys. Finally, we characterized complex kidney lymphatic abnormalities in a genetic mouse model of polycystic kidney disease. Our study provides novel insights into the development of kidney lymphatic vasculature; a system which likely has fundamental roles in renal development, physiology and disease.
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http://dx.doi.org/10.7554/eLife.48183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948954PMC
December 2019

Epidemiology of Autosomal Dominant Polycystic Kidney Disease in Olmsted County.

Clin J Am Soc Nephrol 2020 01 2;15(1):69-79. Epub 2019 Dec 2.

Division of Nephrology and Hypertension,

Background And Objectives: The prevalence of autosomal dominant polycystic kidney disease (ADPKD) remains controversial. Incidence rates in Olmsted County, Minnesota, during 1935-1980 were previously reported. The current work extends this study to 2016.

Design, Setting, Participants, & Measurements: The Rochester Epidemiology Project and radiology databases of Mayo Clinic and Olmsted Medical Center (healthcare providers for Olmsted County) were searched to identify all subjects meeting diagnostic criteria for definite, likely, and possible ADPKD. Annual incidence rates were calculated using incident cases during 1980-2016 as numerator and age- and sex-specific estimates of the population of Olmsted County as denominator. Point prevalence was calculated using prevalence cases as numerator and age- and sex-specific estimates of the population of Olmsted County on January 1, 2010 as denominator. Survival curves from the time of diagnosis were compared with expected survival of the Minnesota population.

Results: The age- and sex-adjusted annual incidence of definite and likely ADPKD diagnosis during 1980-2016 was 3.06 (95% CI, 2.52 to 3.60) per 100,000 person-years, which is 2.2 times higher than that previously reported for 1935-1980 (1.38 per 100,000 person-years). The point prevalence of definite or likely ADPKD on January 1, 2010 was 68 (95% CI, 53.90 to 82.13) per 100,000 population. Much higher incidence rates and point prevalence were obtained when possible ADPKD cases were included. Contrary to the previous Olmsted County study, patient survival in this study was not different from that in the general population.

Conclusions: The point prevalence of definite and likely ADPKD observed in this study is higher than those reported in the literature, but lower than genetic prevalence based on estimates of disease expectancy or on analysis of large population-sequencing databases.
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http://dx.doi.org/10.2215/CJN.05900519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946081PMC
January 2020

The role of DNA damage as a therapeutic target in autosomal dominant polycystic kidney disease.

Expert Rev Mol Med 2019 11 26;21:e6. Epub 2019 Nov 26.

Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, SydneyNSW2145, Australia.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disease and is caused by heterozygous germ-line mutations in either PKD1 (85%) or PKD2 (15%). It is characterised by the formation of numerous fluid-filled renal cysts and leads to adult-onset kidney failure in ~50% of patients by 60 years. Kidney cysts in ADPKD are focal and sporadic, arising from the clonal proliferation of collecting-duct principal cells, but in only 1-2% of nephrons for reasons that are not clear. Previous studies have demonstrated that further postnatal reductions in PKD1 (or PKD2) dose are required for kidney cyst formation, but the exact triggering factors are not clear. A growing body of evidence suggests that DNA damage, and activation of the DNA damage response pathway, are altered in ciliopathies. The aims of this review are to: (i) analyse the evidence linking DNA damage and renal cyst formation in ADPKD; (ii) evaluate the advantages and disadvantages of biomarkers to assess DNA damage in ADPKD and finally, (iii) evaluate the potential effects of current clinical treatments on modifying DNA damage in ADPKD. These studies will address the significance of DNA damage and may lead to a new therapeutic approach in ADPKD.
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http://dx.doi.org/10.1017/erm.2019.6DOI Listing
November 2019

Correction to: Recent advances in the identification and management of inherited hyperoxalurias.

Urolithiasis 2020 Feb;48(1):93

Mayo Clinic, Rochester, MN, USA.

The original version of this article unfortunately contained a mistake. On page 84, the dose for oral potassium citrate is incorrectly written as "0.1 mg/kg/day divided BID-QID for children, 30-60 mg per day divided BID-QID for adults".
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http://dx.doi.org/10.1007/s00240-019-01166-6DOI Listing
February 2020

Synergistic Genetic Interactions between and Result in an ARPKD-Like Phenotype in Murine Models.

J Am Soc Nephrol 2019 11 19;30(11):2113-2127. Epub 2019 Aug 19.

Department of Biochemistry and Molecular Biology, Mayo Graduate School of Biomedical Sciences, Rochester, Minnesota;

Background: Autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD) are genetically distinct, with ADPKD usually caused by the genes or (encoding polycystin-1 and polycystin-2, respectively) and ARPKD caused by (encoding fibrocystin/polyductin [FPC]). Primary cilia have been considered central to PKD pathogenesis due to protein localization and common cystic phenotypes in syndromic ciliopathies, but their relevance is questioned in the simple PKDs. ARPKD's mild phenotype in murine models versus in humans has hampered investigating its pathogenesis.

Methods: To study the interaction between and , including dosage effects on the phenotype, we generated digenic mouse and rat models and characterized and compared digenic, monogenic, and wild-type phenotypes.

Results: The genetic interaction was synergistic in both species, with digenic animals exhibiting phenotypes of rapidly progressive PKD and early lethality resembling classic ARPKD. Genetic interaction between and depended on dosage in the digenic murine models, with no significant enhancement of the monogenic phenotype until a threshold of reduced expression at the second locus was breached. loss did not alter expression, maturation, or localization of the ADPKD polycystin proteins, with no interaction detected between the ARPKD FPC protein and polycystins. RNA-seq analysis in the digenic and monogenic mouse models highlighted the ciliary compartment as a common dysregulated target, with enhanced ciliary expression and length changes in the digenic models.

Conclusions: These data indicate that FPC and the polycystins work independently, with separate disease-causing thresholds; however, a combined protein threshold triggers the synergistic, cystogenic response because of enhanced dysregulation of primary cilia. These insights into pathogenesis highlight possible common therapeutic targets.
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http://dx.doi.org/10.1681/ASN.2019020150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830782PMC
November 2019

Presymptomatic Screening for Intracranial Aneurysms in Patients with Autosomal Dominant Polycystic Kidney Disease.

Clin J Am Soc Nephrol 2019 08 30;14(8):1151-1160. Epub 2019 Jul 30.

Division of Nephrology and Hypertension and Departments of

Background And Objectives: Intracranial aneurysm rupture is the most devastating complication of autosomal dominant polycystic kidney disease. Whether selective or widespread intracranial aneurysm screening is indicated remains controversial.

Design, Setting, Participants & Measurements: Records of 3010 patients with autosomal dominant polycystic kidney disease evaluated at the Mayo Clinic between 1989 and 2017 were reviewed. Those who had presymptomatic magnetic resonance angiography screening were included.

Results: Ninety-four intracranial aneurysms were diagnosed in 75 of 812 (9%) patients who underwent magnetic resonance angiography screening. Sex, age, race, and genotype were similar in the groups with and without aneurysms; hypertension and history of smoking were more frequent in the aneurysm group. Twenty-nine percent of patients with aneurysms compared with 11% of those without aneurysms had a family history of subarachnoid hemorrhage (<0.001). Most aneurysms were small (median diameter =4 mm; range, 2-12 mm); 85% were in the anterior circulation. During a total imaging follow-up of 469 patient-years, intracranial aneurysms were detected in five patients; eight intracranial aneurysms grew (median =2 mm; range, 1-3 mm). During a total clinical follow-up of 668 patient-years, seven patients had preemptive clipping or coil embolization; no intracranial aneurysms ruptured. During a total clinical follow-up of 4783 patient-years in 737 patients with no intracranial aneurysm detected on the first magnetic resonance angiography screening, two patients had an intracranial aneurysm rupture (0.04 per 100 person-years; 95% confidence interval, 0 to 0.10). The rate of intracranial aneurysm rupture in large clinical trials of autosomal dominant polycystic kidney disease was 0.04 per 100 patient-years (95% confidence interval, 0.01 to 0.06).

Conclusions: Intracranial aneurysms were detected by presymptomatic screening in 9% of patients with autosomal dominant polycystic kidney disease, more frequently in those with familial history of subarachnoid hemorrhage, hypertension, or smoking. None of the patients with and two of the patients without aneurysm detection on screening suffered aneurysmal ruptures. The overall rupture rate in our autosomal dominant polycystic kidney disease cohort was approximately five times higher than that in the general population.
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http://dx.doi.org/10.2215/CJN.14691218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682820PMC
August 2019

Bacterial Cholangitis in Autosomal Dominant Polycystic Kidney and Liver Disease.

Mayo Clin Proc Innov Qual Outcomes 2019 Jun 27;3(2):149-159. Epub 2019 May 27.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN.

Objective: To describe first episodes of bacterial cholangitis complicating autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (ADPLD) and to identify risk factors for cholangitis episodes among patients with ADPKD-associated polycystic liver disease (PLD).

Patients And Methods: We searched the electronic medical records at our tertiary referral center for episodes of cholangitis in patients with ADPKD or ADPLD from January 1, 1996, through June 30, 2017. Cases were categorized as suspected or definite cholangitis by expert review. Clinical, laboratory, and radiologic data were manually abstracted. A nested case-control study was conducted to investigate risk factors for cholangitis in patients with ADPKD.

Results: We identified 29 cases of definite or suspected cholangitis complicating PLD (24 with ADPKD-associated PLD and 5 with ADPLD). Among patients with definite cholangitis in ADPKD-associated PLD (n=19) vs ADPLD (n=4), the mean ± SD age was 62.4±12.2 vs 55.1±8.6 years, and 9 (47.4%) vs 0 (0%), respectively, were male. The odds of gallstones (odds ratio [OR], 21.6; 95% CI, 3.17-927; <.001), prior cholecystectomy (OR, 12.2; 95% CI, 1.59-552; =.008), duodenal diverticulum (OR, 13.5; 95% CI, 2.44 to not estimable; =.004), type 2 diabetes mellitus (OR, 6.41; 95% CI, 1.01 to not estimable; =.05), prior endoscopic retrograde cholangiopancreatography (OR, 14.0; 95% CI, 1.80-631; =.005), and prior kidney transplant (OR, 8.06; 95% CI, 1.72-76.0; =.004) were higher in patients with ADPKD-associated PLD with definite cholangitis compared to controls.

Conclusion: Gallstones, prior cholecystectomy, duodenal diverticulosis, type 2 diabetes mellitus, prior endoscopic retrograde cholangiopancreatography, and prior kidney transplant constituted risk factors for cholangitis among patients with ADPKD-associated PLD.
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http://dx.doi.org/10.1016/j.mayocpiqo.2019.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543502PMC
June 2019

International consensus statement on the diagnosis and management of autosomal dominant polycystic kidney disease in children and young people.

Nat Rev Nephrol 2019 11;15(11):713-726

Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University Hospital, Heidelberg, Germany.

These recommendations were systematically developed on behalf of the Network for Early Onset Cystic Kidney Disease (NEOCYST) by an international group of experts in autosomal dominant polycystic kidney disease (ADPKD) from paediatric and adult nephrology, human genetics, paediatric radiology and ethics specialties together with patient representatives. They have been endorsed by the International Pediatric Nephrology Association (IPNA) and the European Society of Paediatric Nephrology (ESPN). For asymptomatic minors at risk of ADPKD, ongoing surveillance (repeated screening for treatable disease manifestations without diagnostic testing) or immediate diagnostic screening are equally valid clinical approaches. Ultrasonography is the current radiological method of choice for screening. Sonographic detection of one or more cysts in an at-risk child is highly suggestive of ADPKD, but a negative scan cannot rule out ADPKD in childhood. Genetic testing is recommended for infants with very-early-onset symptomatic disease and for children with a negative family history and progressive disease. Children with a positive family history and either confirmed or unknown disease status should be monitored for hypertension (preferably by ambulatory blood pressure monitoring) and albuminuria. Currently, vasopressin antagonists should not be offered routinely but off-label use can be considered in selected children. No consensus was reached on the use of statins, but mTOR inhibitors and somatostatin analogues are not recommended. Children with ADPKD should be strongly encouraged to achieve the low dietary salt intake that is recommended for all children.
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http://dx.doi.org/10.1038/s41581-019-0155-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136168PMC
November 2019