Chebib, Fouad T.

Abstract Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease and is characterized by genetic complexity and phenotypic variability. The age of reaching kidney failure (KF) is variable and covers the complete age-spectrum. There is an unmet need for early biomarkers to differentiate between rapid and slow progressors. The PROPKD score identified hypertension before the age of 35 years as a risk factor for rapid kidney function decline. We aim to identify earlier risk factors for rapid disease progression by studying a population of ADPKD patients who reached kidney failure (KF) before the age of 40y. Method This multicentric retrospective study focusses on a unique population (n = 200) of ADPKD patients who reached KF before 40y. Kidney failure (KF) was defined as CKD5 or start of Kidney Replacement Therapy (KRT), whichever came first. Longitudinal data on childhood history, comorbidities and kidney function were collected. Life table and Proportional Hazards analysis were used to assess associations between clinical parameters and time to KF. Results Median age of ADPKD diagnosis was 22.3 (16.5 – 28.6) and median age of KF onset was 36.2 years (32.9-38.7 years). Fourty-seven patients were genotyped (23.5%) of which 38 patients (81.0%) were PKD1T and 8 (17.0%) were PKD1NTand only 1 patient (2.1%) was PKD2. Median age at first urological event was 27.0 (20.7 – 32.0) years. 71 patients (35.5%) had history of UTI's, 67 patients (33.5%) had hemorrhagic cysts on abdominal imaging, 66 patients (33.0%) presented with gross hematuria and 40 patients (25.0%) presented with kidney stones. There was a high prevalence of hypertension (N = 128, 64.0%). Four patients (N = 4/128, 3.1%) had a very early diagnosis of hypertension before the age of 10 years. Hypertension-onset before the age of 18 years correlated with a significantly faster progression (UV HR: 2.07 (1.32 – 3.25)). Conclusion This study describes a unique cohort of ADPKD patients with rapid disease progression. Hypertension at young age (<18) correlated with rapid disease progression, suggesting that ambulatory blood pressure in children might be useful to identify patients at risk for rapidly progressive ADPKD.

ABSTRACT Background Autosomal dominant polycystic kidney disease (ADPKD) presents with variable disease severity and progression. Advanced imaging biomarkers may provide insights into cystic and non-cystic processes leading to kidney failure in different age groups. Methods This pilot study included 39 ADPKD patients with kidney failure, stratified into three age groups (<46, 46–56, >56 years old). Advanced imaging biomarkers were assessed using an automated instance cyst segmentation tool. The biomarkers were compared with an age- and sex-matched ADPKD cohort in early chronic kidney disease (CKD). Results Ht-total parenchymal volume correlated negatively with age at kidney failure. The median Ht-total parenchymal volume was significantly lower in patients older than 56 years. Cystic burden was significantly higher at time of kidney failure, especially in patients who reached it before age 46 years. The cyst index at kidney failure was comparable across age groups and Mayo Imaging Classes. Advanced imaging biomarkers showed higher correlation with Ht-total kidney volume in early CKD than at kidney failure. Cyst index and parenchymal index were relatively stable over 5 years prior to kidney failure, whereas Ht-total cyst volume and cyst parenchymal surface area increased significantly. Conclusion Age-related differences in advanced imaging biomarkers suggest variable pathophysiological mechanisms in ADPKD patients with kidney failure. Further studies are needed to validate the utility of these biomarkers in predicting disease progression and guiding treatment strategies.

Key Points IAs location distribution in patients with ADPKD differ from the ones in non-ADPKD patients IAs in patients with ADPKD are more commonly located in the anterior circulation and in large caliber arteries Because of IA multiplicity and singular IA distribution, patients with ADPKD represent a special population who need to be closely followed Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic condition associated with intracranial aneurysms (IAs). The associated pathophysiology remains unknown, but an association with wall shear stress is suspected. Cerebral arterial location is the principal factor influencing IA natural history. This study aims to compare IA location-specific distribution between ADPKD and non-ADPKD patients. Methods The ADPKD group comprised data from a systematic review of the literature (2016–2020, N =7) and three cohorts: integrated biomedical informatics for the management of cerebral aneurysms, Novosibirsk, and Unruptured Cerebral Aneurysms Study. The non-ADPKD group was formed from the integrated biomedical informatics for the management of cerebral aneurysms, Unruptured Cerebral Aneurysms Study, International Stroke Genetics Consortium, and the Finnish cohort from the literature. Patients and IAs characteristics were compared between ADPKD and non-ADPKD groups, and a meta-analysis for IA locations was performed. Results A total of 1184 IAs from patients with ADPKD were compared with 21,040 IAs from non-ADPKD patients. In total, 78.6% of patients with ADPKD had hypertension versus 39.2% of non-ADPKD patients. A total of 32.4% of patients with ADPKD were smokers versus 31.5% of non-ADPKD patients. In total, 30.1% of patients with ADPKD had a positive family history for IA versus 15.8% of the non-ADPKD patients. Patients with ADPKD showed a higher rate of IA multiplicity (33.2% versus 23.1%). IAs from patients with ADPKD showed a significant predominance across the internal carotid and middle cerebral arteries. Posterior communicating IAs were more frequently found in the non-ADPKD group. The meta-analysis confirmed a predominance of IAs in the patients with ADPKD across large caliber arteries (odds ratio [95% confidence interval]: internal carotid artery: 1.90 [1.10 to 3.29]; middle cerebral artery: 1.18 [1.02–1.36]). Small diameter arteries, such as the posterior communicating, were observed more in non-ADPKD patients (0.21 [0.11–0.88]). Conclusion This analysis shows that IAs diagnosed in patients with ADPKD are more often localized in large caliber arteries from the anterior circulation in comparison with IAs in non-ADPKD patients. It shows that primary cilia driven wall shear stress vessel remodeling to be more critical in cerebral anterior circulation large caliber arteries.

Key Points Asymptomatic pyuria is associated with kidney failure and faster kidney function decline irrespective of the ADPKD gene and cystic growth. The eGFR decline occurred after detection of asymptomatic pyuria without significant changes in the rate of total kidney volume growth. This study supports the use of asymptomatic pyuria as an enriching prognostic biomarker to predict faster disease progression. Background Autosomal dominant polycystic kidney disease (ADPKD) has phenotypic variability only partially explained by established biomarkers that do not readily assess pathologically important factors of inflammation and kidney fibrosis. We evaluated asymptomatic pyuria (AP), a surrogate marker of inflammation, as a biomarker for disease progression. Methods We performed a retrospective cohort study of adult patients with ADPKD. Patients were divided into AP and no pyuria (NP) groups. We evaluated the effect of pyuria on kidney function and kidney volume. Longitudinal models evaluating kidney function and kidney volume rate of change with respect to incidences of AP were created. Results There were 687 included patients (347 AP, 340 NP). The AP group had more women (65% versus 49%). Median ages at kidney failure were 86 and 80 years in the NP and AP groups (log rank, P =0.49), respectively, for patients in Mayo Imaging Class (MIC) 1A–1B as compared with 59 and 55 years for patients in MIC 1C–1D–1E (log rank, P =0.02), respectively. Compared with the NP group, the rate of kidney function (ml/min per 1.73 m 2 per year) decline shifted significantly after detection of AP in the models, including all patients (−1.48; P <0.001), patients in MIC 1A–1B (−1.79; P <0.001), patients in MIC 1C–1D–1E (−1.18; P <0.001), and patients with PKD1 (−1.04; P <0.001). Models evaluating kidney volume rate of growth showed no change after incidence of AP as compared with the NP group. Conclusions AP is associated with kidney failure and faster kidney function decline irrespective of the ADPKD gene, cystic burden, and cystic growth. These results support AP as an enriching prognostic biomarker for the rate of disease progression.

Polycystic kidney disease (PKD) is the most common monogenic kidney disorder and an important cause of end stage renal disease. Vascular abnormalities are the most important non‐cystic complication and contribute to renal disease progression. Homocysteine (Hcy)‐mediated endothelial dysfunction (ED) and oxidative stress are evident early on, but the underlying mechanisms remain unknown. We hypothesized that abnormalities in Hcy metabolism are responsible for the increased levels, leading to Hcy‐induced ED from early stages of PKD. Methods We investigated the Hcy metabolic pathway (transulfuration/remethylation fig. 1) and downstream effects ‐main sources of renal tubular (RT) and endothelial cell (EC) reactive oxygen species (ROS), NADPH oxidase 4, (NOX4) and mitochondria‐ in 4‐week‐old PCK and Sprague‐Dawley (SD) control rats (n=12 each). Kidneys were harvested, frozen in liquid nitrogen, or preserved in formalin for metabolomics and ex‐vivo studies. Twenty‐four‐hour urine and terminal blood samples were collected for metabolite analysis and chemistries. Plasma folic acid, vitamin B12, and Hcy were determined by ELISA. Hcy pathway metabolites (betaine, dimethylglycine) were determined by 1 HNMR. Endothelial NO (eNOS) and oxidative stress were assessed by double immunofluorescence staining for CD31/eNOS and CD31/NOX4, respectively. RT and EC mitochondrial structure was assessed by electron microscopy. Results Serum creatinine and BUN remained unchanged, yet kidney weight/body weight ratio were increased in PCK. eNOS immunoreactivity was lower in PCK vs SD. Plasma Hcy and urine excretion of methyl donor betaine were elevated in PCK, and Hcy positively correlated with urine betaine. Plasma betaine was similar between the groups, but its tissue concentration was lower in PCK, which may lead to betaine insufficiency, impaired betaine dependent remethylation, and hyperhomocysteinemia. Contrarily, tissue glutathione concentration was higher in PCK vs SD, and plasma folate and vitamin B12 were similar, arguing against a defect in the transsulfuration or folate‐dependent remethylation pathways. RT NOX4 expression and immunoreactivity were increased in PCK compared to SD, in association with renal oxidative stress. PCK had increased number of CD31/NOX4 positive cells in peritubular capillaries, indicating increased EC ROS production. Collecting duct and EC mitochondria were swollen and showed cristae remodeling. Conclusion In PKD, early elevation in Hcy is likely related to betaine insufficiency and impaired betaine‐dependent remethylation may be responsible for the early elevation of Hcy. NOX4 and mitochondria abnormalities may be important contributors to oxidative stress and disease severity. Our data suggests these may not only be early vascular disease markers, but also play an important pathogenic role in vascular complications associated with PKD, and contribute to renal disease progression. Support or Funding Information R25‐DK101405, NIDDK P30 DK090728, NIDDK P30 DK 106912 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Disruption of intracellular calcium likely underlies the upregulation of cyclic AMP (cAMP) signaling and the proliferative and secretory phenotype of the cystic epithelium in ADPKD. However, the mechanisms by which polycystins reduce cytoplasmic calcium remain elusive. Impaired flow‐induced calcium entry through ciliary polycystin complex has been previously proposed as a pathogenic mechanism, but newer evidence suggests the involvement of polycystins in modulation of other mechanosensitive ion channels such as Piezo1, the newly‐identified stretch‐activated non‐selective cation channel. We hypothesized that polycystins, through their physical and functional interaction with Piezo1, modulate various cellular responses to mechanical stimulation. Piezo1 was expressed in both wild type mouse inner medullary collecting duct cells (mIMCD3) cells and PKD2 null cells (~3 fold higher than wild type). Wild type mIMCD3 cells were stably transfected with genetically encoded biosensors, jRGeco1a and Flamindo2, to study spatiotemporal dynamics of calcium and cAMP during live cell imaging, respectively. Piezo1 activation by Yoda1 increased cytoplasmic calcium and simultaneously lowered forskolin‐induced cAMP (Figure 1A). Additionally, exerting physiological fluid shear stress (FSS) (ibidi pump system) led to reduction in cAMP (Figure 1B). Both Yoda1 and FSS lead to an increase in ATP release in mIMCD3 cells (Figure 1C). Furthermore, Yoda1 significantly reduced forskolin‐induced in vitro cystogenesis by 68% in WT and by 48% in PKD2 null mIMCD3 cells (Figure 1D). These results suggest that Piezo1 is involved in renal cystogenesis by controlling FSS‐induced calcium entry. Further studies are required to determine in vivo effect of Piezo1 on renal cystogenesis. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

BACKGROUND A 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. METHODS The 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. RESULTS Both 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. CONCLUSION The 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. FUNDING NIDDK grants: Mayo DK058816 and DK090728; CRISP DK056943, DK056956, DK056957, and DK056961; and HALT PKD DK062410, DK062408, DK062402, DK082230, DK062411, and DK062401.

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 ( P <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, de novo 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.