Autosomal Dominant Polycystic Kidney Disease Patients Research Articles

Cerebrovascular Pulsatility Index Is Reduced in Autosomal Dominant Polycystic Kidney Disease

Introduction: Cerebrovascular dysfunction, characterized by increased brain pulsatile flow, reduced cerebrovascular reactivity, and cerebral hypoperfusion precedes the onset of dementia and is linked to cognitive dysfunction. Autosomal dominant polycystic kidney disease (ADPKD) may increase the risk of dementia, and intracranial aneurysms are more prevalent in ADPKD patients. However, cerebrovascular function has not been previously characterized in patients with ADPKD. Methods: Using transcranial Doppler, we compared middle cerebral artery (MCA) pulsatility index (PI, cerebrovascular stiffness) and MCA blood velocity response to hypercapnia (normalized for blood pressure and end-tidal CO₂, cerebrovascular reactivity) in patients with early-stage ADPKD versus age-matched healthy controls. We also administered the NIH cognitive toolbox (cognitive function) and measured carotid-femoral pulse-wave velocity (PWV, aortic stiffness). Results: Fifteen participants with ADPKD (9F, 27 ± 4 yrs, eGFR: 106 ± 22 mL/min/1.73 m²) were compared to 15 healthy controls (8F, 29 ± 4 yrs, eGFR: 109 ± 14 mL/min/1.73 m²). MCA PI was unexpectedly lower in ADPKD (0.71 ± 0.07) versus controls (0.82 ± 0.09 AU; p < 0.001); however, normalized MCA blood velocity in response to hypercapnia did not differ between groups (2.0 ± 1.2 vs. 2.1 ± 0.8 %Δ/mm Hg; p = 0.85). Lower MCA PI was associated with a lower crystalized composite score (cognition), which persisted after adjustment for age, sex, eGFR, and education (β = 0.58, p = 0.007). There was no association of MCA PI with carotid-femoral PWV (r = 0.01, p = 0.96), despite greater carotid-femoral PWV in ADPKD, suggesting MCA PI reflects vascular properties other than arterial stiffness (such as low wall shear stress) in ADPKD. Discussion/Conclusion: MCA PI is lower in patients with ADPKD. Follow-up research on this observation is merited as low PI has been associated with intracranial aneurysm in other populations.

The safety and efficacy of tolvaptan in the treatment of patients with autosomal dominant polycystic kidney disease: A systematic review and meta-analysis

BackgroundThe irreversible progression of autosomal dominant polycystic kidney disease (ADPKD) to end-stage renal disease (ESRD) is delayed by tolvaptan. Therefore, we aim to systematically estimate and evaluate the efficacy and safety of tolvaptan in the treatment of ADPKD. MethodsTwo reviewers independently searched all published randomized controlled trials studies in PubMed, EMBASE, Web of Science and Cochrane databases, extracted data, assessed bias risk and rated the quality of evidence. Data were analyzed by the RevMan software. ResultsWe identified 8 trials including 2135 patients. Both of the decline of estimated glomerular filtration rate (eGFR) [MD=1.89, 95% CI (0.74, 3.04), P=0.001] and total kidney volume (TKV) [MD=−3.32, 95% CI (−4.57, −2.07), P<0.001] were delayed in tolvaptan group compared with placebo group in ADPKD patients. The use of tolvaptan delayed TKV progression in the different-month subgroups [MD=−69.99, 95% CI (−91.05, −48.94), P<0.001]. Tolvaptan reduced renal pain [RR=0.66, 95% CI (0.54, 0.81), P<0.001] and hematuria events [RR=0.55, 95% CI (0.41, 0.74), P<0.001] in ADPKD patients. However, the prevalence of thirst [RR=2.75, 95% CI (2.34, 3.24), P<0.001] and nocturia events [RR=3.01, 95% CI (1.27, 7.11), P=0.01] were increased in tolvaptan group. There is no significant difference of hypertension events [RR=0.92, 95% CI (0.82, 1.03), P=0.13] in tolvaptan group compared placebo group. ConclusionsThis meta-analysis suggests that tolvaptan may improve clinical progression in patients with ADPKD without significantly increasing the risk of adverse reactions.

Clinical features and prognosis of autosomal dominant polycystic kidney disease with cerebrovascular complications.

This retrospective study was used to evaluate the clinical and imaging characteristics and the prognosis of autosomal dominant polycystic kidney disease (ADPKD) with cerebrovascular complications. We retrospectively analyzed 30 patients with ADPKD complicated with intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), unruptured intracranial aneurysms (UIAs), or Moyamoya disease (MMD) who were admitted to Jinling Hospital from January 2001 to January 2022. We analyzed the clinical manifestations and imaging characteristics of ADPKD patients with cerebrovascular complications and followed up on their long-term outcomes. 30 patients, 17 men and 13 women, with an average age of 47.5 (40.0, 54.0) years were included in this study, including 12 cases of ICH, 12 cases of SAH, 5 cases of UIA, and 1 case of MMD. The 8 patients who died during follow-up had a lower Glasgow Coma Scale (GCS) on admission (p=0.024) and a significantly higher serum creatinine (p=0.004) and blood urea nitrogen (p=0.006) than the 22 patients with long-term survival. Intracranial aneurysms, SAH, and ICH are the most common cerebrovascular diseases in ADPKD. Patients with low GCS score or worse renal function have a poor prognosis, which can lead to disability and even death.

Review of Treatments for ADPKD on Tolvaptan and ketogenic Dietary Intervention as a Novel Therapy

Autosomal dominant polycystic kidney disease (ADPKD), the most prevalent genetic kidney disease, affected millions of individuals worldwide. And it is also one of the most prevalent causes of kidney failures and transplants. Previously, in many years, mitigating its symptoms had been the only treatment for this disease. After more than a decade after the early clinical studies of medicines for ADPKD began, the first medication that may successfully delay the course of the condition is now on the market. Due to the severe side effects and high cost of tolvaptan, it cannot be considered a full success, but rather the beginning of therapeutic research. More recently, enlightened by the discovery of the defective metabolism of PKD related cells, researchers have been designing dietary plans and new lifestyles for ADPKD patients to slow down or even halt the disease progression. Current outcomes have been promising. This article will address the best practices for treating ADPKD patients, with a focus on medications that have been proved to be beneficial in preserving kidneys function and structure.

Recent updates in therapeutic approach using tolvaptan for autosomal dominant polycystic kidney disease.

As a genetic disease, there has been a long-standing effort to identify therapeutic options for autosomal dominant polycystic kidney disease (ADPKD). Following the development of tolvaptan, a vasopressin 2 receptor antagonist, the treatment strategy for ADPKD patients with rapid disease progression has been changed with a disease-targeted approach. Tolvaptan showed significant efficacy in preserving kidney function and reducing the total kidney volume (TKV) growth rate. These effects were especially pronounced in patients with more severe clinical phenotypes, such as higher TKV and rapidly declining kidney function. Despite the therapeutic effects of tolvaptan, aquaretic symptoms are unavoidable side effects related to the mechanism of the drug and are also directly related to the quality of life. A shared decision-making process could be a valuable strategy for reducing the incidence of side effects and improving medication adherence. Herein, we aimed to review overall clinical trials for applying tolvaptan and suggest important factors during the shared decision-making process.

Parasympathetic activity and total fibrotic kidney in autosomal-dominant polycystic kidney disease patients: a pilot study

PurposeRenin–angiotensin system hyperactivation in autosomal-dominant polycystic kidney disease (ADPKD) patients leads to early hypertension. Cystic enlargement probably causes parenchymal hypoxia, renin secretion, and endothelial dysfunction. Sympathetic and parasympathetic balance is altered in this condition, especially during the night, also affecting blood pressure circadian rhythm. Aim of this study was to evaluate sympathetic/parasympathetic balance using heart rate variability (HRV) parameters and find a correlation between HRV and renal damage progression, as total kidney volume enlargement, in ADPKD patients.MethodsSixteen adult ADPKD patients were enrolled in the study. Eleven patients (68.8%) were male, and the median age was 42 years (IQR 36–47.5). HRV parameters were calculated using 24 h-ECG Holter. A kidney magnetic resonance imaging (MRI) scan 3 Tesla was performed to evaluate total kidney volume (TKV) and total fibrotic volume (TFV).ResultsA statistically significant positive linear correlation was observed between length of kidneys and frequency domain parameters as low frequency (LF) (r = 0.595, p < 0.05) and LFday (r = 0.587, p < 0.05). Moreover, a statistically significant positive linear correlation exists between high frequency (HF) and TFV (r = 0.804, p < 0.01) or height-adjusted (ha) TFV (r = 0.801, p < 0.01). Finally, we found a statistically significant positive linear correlation between HFnight and TKV (r = 0.608, p < 0.05), ha-TKV (r = 0.685, p < 0.01), TFV (r = 0.594, p < 0.05), and ha-TFV (r = 0.615, p < 0.05).ConclusionWe suppose that the increase in TKV and TFV could lead to a parasympathetic tone hyperactivation, probably in response to hypoxic stress and vasoconstriction due to cystic enlargement.

Diffusion magnetic resonance imaging for kidney cyst volume quantification and non-cystic tissue characterisation in ADPKD.

Beyond total kidney and cyst volume (TCV), non-cystic tissue plays an important role in autosomal dominant polycystic kidney disease (ADPKD) progression. This study aims at presenting and preliminarily validating a diffusion MRI (DWI)-based TCV quantification method and providing evidence of DWI potential in characterising non-cystic tissue microstructure. T2-weighted MRI and DWI scans (b = 0, 15, 50, 100, 200, 350, 500, 700, 1000; 3 directions) were acquired from 35 ADPKD patients with CKD stage 1 to 3a and 15 healthy volunteers on a 1.5T scanner. ADPKD classification was performed using the Mayo model. DWI scans were processed by mono- and segmented bi-exponential models. TCV was quantified on T2-weighted MRI by the reference semi-automatic method and automatically computed by thresholding the pure diffusivity (D) histogram. The agreement between reference and DWI-based TCV values and the differences in DWI-based parameters between healthy and ADPKD tissue components were assessed. There was strong correlation between DWI-based and reference TCV (rho = 0.994, p < 0.001). Non-cystic ADPKD tissue had significantly higher D, and lower pseudo-diffusion and flowing fraction than healthy tissue (p < 0.001). Moreover, apparent diffusion coefficient and D values significantly differed by Mayo imaging class, both in the whole kidney (Wilcoxon p = 0.007 and p = 0.004) and non-cystic tissue (p = 0.024 and p = 0.007). DWI shows potential in ADPKD to quantify TCV and characterise non-cystic kidney tissue microstructure, indicating the presence of microcysts and peritubular interstitial fibrosis. DWI could complement existing biomarkers for non-invasively staging, monitoring, and predicting ADPKD progression and evaluating the impact of novel therapies, possibly targeting damaged non-cystic tissue besides cyst expansion. This study shows diffusion-weighted MRI (DWI) potential to quantify total cyst volume and characterise non-cystic kidney tissue microstructure in ADPKD. DWI could complement existing biomarkers for non-invasively staging, monitoring, and predicting ADPKD progression and evaluating the impact of novel therapies, possibly targeting damaged non-cystic tissue besides cyst expansion. • Diffusion magnetic resonance imaging shows potential to quantify total cyst volume in ADPKD. • Diffusion magnetic resonance imaging might allow to non-invasively characterise non-cystic kidney tissue microstructure. • Diffusion magnetic resonance imaging-based biomarkers significantly differ by Mayo imaging class, suggesting their possible prognostic value.

V03-11 LAPAROSCOPIC NEPHRECTOMY FOR POLYCYSTIC KIDNEY: A VIDEO-ILLUSTRATED CASE SERIES OF TRANSPERITONEAL AND RETROPERITONEAL APPROACHES

You have accessJournal of UrologyCME1 Apr 2023V03-11 LAPAROSCOPIC NEPHRECTOMY FOR POLYCYSTIC KIDNEY: A VIDEO-ILLUSTRATED CASE SERIES OF TRANSPERITONEAL AND RETROPERITONEAL APPROACHES Daniele D'Agate, Giorgio Calleris, Marco Allasia, Marco Oderda, Alessandro Marquis, Giancarlo Marra, Federico Vitiello, Federico Lavagno, Matteo de Bellis, Gabriele Montefusco, Francesco Bracco, and Paolo Gontero Daniele D'AgateDaniele D'Agate More articles by this author , Giorgio CallerisGiorgio Calleris More articles by this author , Marco AllasiaMarco Allasia More articles by this author , Marco OderdaMarco Oderda More articles by this author , Alessandro MarquisAlessandro Marquis More articles by this author , Giancarlo MarraGiancarlo Marra More articles by this author , Federico VitielloFederico Vitiello More articles by this author , Federico LavagnoFederico Lavagno More articles by this author , Matteo de BellisMatteo de Bellis More articles by this author , Gabriele MontefuscoGabriele Montefusco More articles by this author , Francesco BraccoFrancesco Bracco More articles by this author , and Paolo GonteroPaolo Gontero More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003241.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Both transperitoneal (TP) and retroperitoneal (RP) laparoscopic nephrectomies (NT) have been described for autosomal dominant polycystic kidney disease (APKD), and no conclusive evidence exists about the best approach. We present in this video the step-by-step procedure for both techniques. Perioperative data of a single-institutional case-series are reported. METHODS: A retrospective review of the NTs in APKD patients in between June 2020 and April 2022 was conducted. The TP approach requires the positioning of three 12-mm ports and one 5-mm ports, the mobilisation of the colon, the incision of Gerota’s fascia and the development of the psoas plane to identify the renal pedicle. Renal vessels and ureter are clipped by Hem-o-lok ® and divided. The RP approach usually requires the positioning of a first 12-mm trocar at the apex of the XII rib; the RP space is developed using a dedicated balloon; two more 12-mm trocars are placed at the posterior axillary line and in the iliac fossa. The psoas plane allows an early access to the renal pedicle; the renal vessels and the ureter are ligated by Hem-o-lok ® and divided. In both approaches, the puncture and the suction of the major cysts is frequent during dissection; adrenal-sparing approach was feasible in all cases; a modified Gibson incision is made for kidney extraction. RESULTS: Six consecutive patients were enrolled, 3 of whom were treated by TP and 3 by RP-NT. Two patients were on haemodialysis and 2 had already undergone a renal transplantation. Mean age was 49 and 57 years, maximum kidney diameter was 28.25 and 30 cm and mean operative time was 171 and 210 min, respectively for RP and TP. No conversion to open surgery was made. The reason for NT was represented by symptomatic polycystic kidney in 5 cases; surgery was required solely in preparation to kidney transplantation in 1 TP case. No Clavien 3 grade complications or greater were recorded; postoperative sepsis occurred in 2 TP patients, haematoma in 1 TP and 1 RP cases, blood transfusions were required in 2 TP and 1 RP cases, 1 RP patient experienced a deep venous thrombosis. The hospitalization time ranged from 5 to 31 days. No significant worsening of the renal function was observed at discharge. CONCLUSIONS: At present, the scarce existing data do not suggest the superiority of an approach over the other one. Both RP and TP approaches for nephrectomy of polycystic kidneys are feasible in experienced hands and the choice must be tailored on patient characteristics and surgeon’s preference. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e249 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Daniele D'Agate More articles by this author Giorgio Calleris More articles by this author Marco Allasia More articles by this author Marco Oderda More articles by this author Alessandro Marquis More articles by this author Giancarlo Marra More articles by this author Federico Vitiello More articles by this author Federico Lavagno More articles by this author Matteo de Bellis More articles by this author Gabriele Montefusco More articles by this author Francesco Bracco More articles by this author Paolo Gontero More articles by this author Expand All Advertisement PDF downloadLoading ...

Assessment of Hypertension in Children with Autosomal Dominant Polycystic Kidney Disease; Single-Center Experience

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common hereditary renal cystic diseases. Althoughits clinical manifestations usually occur in adulthood, hypertension (HT) is known to develop in most patients before the decline inrenal function and it is associated with faster progression to end stage kidney disease (ESKD). We investigated ambulatory bloodpressure monitoring (ABPM) results of 23 patients with ADPKD, followed up in the Pediatric Nephrology Clinic of Ondokuz MayısUniversity Medical Faculty Hospital. Patients’ demographic characteristics, laboratory and ultrasonography (US) results, officeblood pressure, and ABPM measurements were evaluated. The parameters of gender, age, increased kidney size, proteinuria,glomerular filtration rate (GFR) was compared in hypertensive and non-hypertensive group. Twenty three patients (13 girls, tenboys) with a mean age of 11.94±4.01 (min-max: 4.6-18) years and a female/male ratio of 1.3/1 were examined. Ultrasound revealedincreased kidney sizes in 12 patients (52.2%) and multiple cysts in the bilateral kidneys in 20 patients (87%). Mild to moderateproteinuria was detected in 7 patients (30.4%). The HT ratio of patients was 52.2% and 39.1% when assessed with office bloodpressure (BP) measurement and ABPM respectively. A non-dipper pattern was established in 14 patients (60.9%). Gender, age,increased kidney size, proteinuria, GFR did not differ significantly between ADPKD patients with and without ambulatory HT. Thisstudy shows that nearly half of children with ADPKD have HT by ABPM. BP should be regularly screened by ABPM in all pediatricADPKD patients.

Nutritional Status is Associated With Preserved Kidney Function in Patients With Autosomal Dominant Polycystic Kidney Disease

Malnutrition is a common complication in autosomal dominant polycystic kidney disease (ADPKD). We examined whether nutritional status is associated with the preservation of kidney function, using a cohort of typical ADPKD. We enrolled ambulatory ADPKD patients in 9 tertiary medical centers in Korea from May 2019 to December 2021. We excluded patients who were aged less than 18years, who had known end-stage kidney disease at the time of enrollment, who had a diagnosis of atypical ADPKD, and who were Tolvaptan users. The primary outcome was an estimated glomerular filtration rate (eGFR) decline >3mL/min/1.73m2, based on nutritional status assessed by subjective global assessment (SGA). We also evaluated an eGFR decline >1mL/min/1.73m2, an increase in urine protein-creatinine ratio (UPCR)>0, and an increase in UPCR >0.3 as secondary outcomes, based on SGA after the 1-year follow-up. A logistic regression (LR) model was used to calculate the odds ratio (OR) for the primary outcome. Because there were differences in several baseline variables, such as Mayo classification, serum hemoglobin, serum creatinine, and UPCR between SGA groups, we matched propensity scores. In total, 805 patients were prospectively enrolled. Among them, 236 patients who had 1-year follow-up data and typical imaging findings were analyzed to evaluate the effect of nutritional status on kidney function. SGA was used to assess the nutritional status. The mean age was 45.0±13.3years, and 49.6% of the patients were female. The mean eGFR was 81.9mL/min/1.73m2. Among the 236 patients, 91 (38.6%) experienced a 1-year eGFR decline >3mL/min/1.73m2. When a multivariable LR was applied, SGA 3-6 was identified as a significant factor related to a 1-year eGFR decline >3mL/min/1.73m2 (adjusted OR=1.22 [1.04-1.43]; P=.017). Despite matching propensity scores, the 1-year eGFR decline >3mL/min/1.73m2 was still higher in the SGA 3-6 group regardless of proteinuria. Good nutritional status is associated with better-preserved kidney function in non-obese typical ADPKD patients who do not take Tolvaptan.

Identifying the main predictors of urine output in autosomal-dominant polycystic kidney disease (ADPKD) patients taking tolvaptan.

Few works have analyzed factors associated with urine output in ADPKD patients taking tolvaptan (TVP). We selected 24-h urine samples from ADPKD patients treated withTVP. Urine osmolality/creatinine ratio was used as estimator of urinary osmolar load. We included 127 urine samples from 61 patients. After TVP, urine output doubled with a parallel reduction in urine solute concentration. However, when expressed as urine solute/creatinine ratios, no significant changes were observed. Daily osmolar load and osmolality/creatinine ratio did not change significantly. Before TVP, urine output was positively correlated with body weight and urine osmolality/creatinine ratio and negatively with eGFR, urine morning osmolality, and 24-h urine-calculated osmolality. After TVP, urine output was positively correlated with body weight, eGFR and negatively with age. There was a poor correlation with urine-calculated osmolality. We constructed a predictor model using mixed-effects modeling and we found that urine output was related to lower age, higher body weight, higher eGFR, and greater doses of TVP. When body weight was removed, urine output was also related to male sex and a higher daily osmolar excretion. Equation of prediction was: Urine output (mL/day) = 2771-52.9 × Age (years) + 58.4 × Weight (kg) + 18.7 × eGFR (mL/min) + 870 (if TVP = 90/30mg) + 517 (if TVP = 60/30mg). Patients taking TVP will undergo an increase about twice in urine production from baseline. Greater doses of TVP cause a progressive increase in urine production. GFR, age, and body weight are the main predictors of future urine output in patients taking TVP.

Low agreement between various eGFR formulae in pediatric and young adult ADPKD patients.

Young autosomal dominant polycystic kidney disease (ADPKD) patients are becoming the new target population for the development of new treatment options. Determination of a reliable equation for estimated glomerular filtration rate (eGFR) from early stages is needed with the promising potential interventional therapies. Prospective and longitudinal study on a cohort of 68 genotyped ADPKD patients (age range 0-23years) with long-term follow-up. Commonly used equations for eGFR were compared for their relative performance. The revised Schwartz formula (CKiD) showed a highly significant decline in eGFR with aging (- 3.31mL/min/1.73 m2/year, P < 0.0001). The recently updated equation by the Schwartz group (CKiDU25) showed a smaller (- 0.90mL/min/1.73 m2/year) but significant (P = 0.001) decline in eGFR with aging and also showed a significant sex difference (P < 0.0001), not observed by the other equations. In contrast, the full age spectrum (FAS) equations (FAS-SCr, FAS-CysC, and the combined) showed no age and sex dependency. The prevalence of hyperfiltration is highly dependent on the formula used, and the highest prevalence was observed with the CKiD Equation(35%). The most widely used methods to calculate eGFR in ADPKD children (CKiD and CKiDU25 equations) were associated with unexpected age or sex differences. The FAS equations were age- and sex-independent in our cohort. Hence, the switch from the CKiD to CKD-EPI equation at the transition from pediatric to adult care causes implausible jumps in eGFR, which could be misinterpreted. Having reliable methods to calculate eGFR is indispensable for clinical follow-up and clinical trials. A higher resolution version of the Graphical abstract is available as Supplementary information.

The association of urinary epidermal growth factors with ADPKD disease severity and progression.

The epidermal growth factor receptor (EGFR) pathway is involved in kidney tissue repair and growth. Preclinical interventional data and scarce human data have suggested a role for this pathway in the pathophysiology of Autosomal Dominant Polycystic Kidney Disease (ADPKD), while other data have suggested that its activation is causally linked to repair of damaged kidney tissue. We hypothesize that urinary EGFR ligands, as a reflection of EGFR activity, are associated with kidney function decline in ADPKD in the context of tissue repair following injury, and as the disease progresses as a sign of insufficient repair. In the present study, we measured the EGFR ligands, EGF and heparin binding-EGF (HB-EGF), in 24-h urine samples of 301 ADPKD patients and 72 age- and sex matched living kidney donors to dissect the role of the EGFR pathway in ADPKD. During a median follow-up of 2.5 years, the association of urinary EGFR ligand excretion with annual change in estimated glomerular filtration rate (eGFR) and height adjusted total kidney volume (htTKV) in ADPKD patients was analyzed using mixed-models methods and the expression of three closely related EGFR family receptors in ADPKD kidney tissue was investigated by immunohistochemistry. Additionally, the effect of reducing renal mass (after kidney donation), was assessed to investigate whether urinary EGF matches this reduction and thus reflects the amount of remaining healthy kidney tissue. At baseline, urinary HB-EGF did not differ between ADPKD patients and healthy controls (p=0.6), whereas a lower urinary EGF excretion was observed in ADPKD patients (18.6 [11.8-27.8] compared to healthy controls (51.0 [34.9-65.4] µg/24h, p<0.001). Urinary EGF was positively associated with baseline eGFR (R=0.54, p<0.001) and a lower EGF was strongly associated with a more rapid GFR decline, even when adjusted for ADPKD severity markers (β = 1.96, p<0.001), whereas HB-EGF was not. Expression of the EGFR, but not other EGFR-related receptors, was observed in renal cysts but was absent in non-ADPKD kidney tissue. Finally, unilateral nephrectomy resulted in a decrease of 46.4 [-63.3 to -17.6]% in urinary EGF excretion, alongside a decrease of 35.2±7.2% in eGFR and 36.8±6.9% in mGFR, whereas maximal mGFR (measured after dopamine induced hyperperfusion) decreased by 46.1±7.8% (all p<0.001). Our data suggest that lower urinary EGF excretion may be a valuable novel predictor for kidney function decline in patients with ADPKD.

Elevated checkpoint inhibitor expression and Treg cell number in autosomal dominant polycystic kidney disease and their correlation with disease parameters and hypertension.

Autosomal dominant polycystic kidney disease (ADPKD) has cancer-like pathophysiology. In this study, we aimed to investigate the phenotype of peripheral blood (PB) T cell subsets and immune checkpoint inhibitor expression of ADPKD patients across different chronic kidney disease (CKD) stages. Seventy-two patients with ADPKD and twenty-three healthy controls were included in the study. The patients were grouped into five different CKD stages, according to glomerular filtration rate (GFR). PB mononuclear cells were isolated and T cell subsets and cytokine production were examined by flow cytometry. CRP levels, height-adjusted total kidney volume (htTKV), rate of hypertension (HT) differed significantly across different GFR stages in ADPKD. T cell phenotyping revealed significantly elevated CD3+ T cells, CD4+, CD8+, double-negative, and double-positive subsets and significantly elevated IFN-γ and TNF-α producing subsets of CD4+, CD8+ cells. The expression of checkpoint inhibitors CTLA-4, PD-1, and TIGIT by T cell subsets was also increased to various extent. Additionally, Treg cell numbers and suppressive markers CTLA-4, PD-1, and TIGIT were significantly elevated in ADPKD patients' PB. Treg CTLA4 expression and CD4CD8DP T cell frequency in patients with HT were significantly higher. Lastly, HT and increased htTKV and higher frequency of PD1+ CD8SP were found to be risk factors for rapid disease progression. Our data provide the first detailed analyses of checkpoint inhibitor expression by PB T cell subsets during stages of ADPKD, and that a higher frequency of PD1+ CD8SP cells is associated with rapid disease progression.

Metabolism-based approaches for autosomal dominant polycystic kidney disease.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) leads to end stage kidney disease (ESKD) through the development and expansion of multiple cysts throughout the kidney parenchyma. An increase in cyclic adenosine monophosphate (cAMP) plays an important role in generating and maintaining fluid-filled cysts because cAMP activates protein kinase A (PKA) and stimulates epithelial chloride secretion through the cystic fibrosis transmembrane conductance regulator (CFTR). A vasopressin V2 receptor antagonist, Tolvaptan, was recently approved for the treatment of ADPKD patients at high risk of progression. However additional treatments are urgently needed due to the poor tolerability, the unfavorable safety profile, and the high cost of Tolvaptan. In ADPKD kidneys, alterations of multiple metabolic pathways termed metabolic reprogramming has been consistently reported to support the growth of rapidly proliferating cystic cells. Published data suggest that upregulated mTOR and c-Myc repress oxidative metabolism while enhancing glycolytic flux and lactic acid production. mTOR and c-Myc are activated by PKA/MEK/ERK signaling so it is possible that cAMPK/PKA signaling will be upstream regulators of metabolic reprogramming. Novel therapeutics opportunities targeting metabolic reprogramming may avoid or minimize the side effects that are dose limiting in the clinic and improve on the efficacy observed in human ADPKD with Tolvaptan.

Blocker displacement amplification-based genetic diagnosis for autosomal dominant polycystic kidney disease and the clinical outcomes of preimplantation genetic testing.

Given that the molecular diagnosis of autosomal dominant polycystic kidney disease (ADPKD) is complicated, we aim to apply blocker displacement amplification (BDA) on the mutational screening of PKD1 and PKD2. A total of 35 unrelated families with ADPKD were recruited from the Center for Reproductive Medicine, Women and Children's Hospital of Chongqing Medical University (Chongqing, China), from October 2018 to October 2021. Long-range PCR followed by next-generation sequencing were applied for resequencing of PKD1 and PKD2, and the putatively disease-causative variants were verified with BDA. The effects of ADPKD on male and female infertility and the factors influencing the clinical outcomes of preimplantation genetic testing (PGT) for ADPKD were investigated. A total of 26 PKD1 variants and 5 PKD2 variants were identified, of which 13 were newly discovered. The BDA system worked effectively for eliminating the interference of pseudogenes in genetic testing of PKD1 (1-33 exons) with different concentrations of genome DNA. The females with ADPKD have no specific infertility factors, while 68.2% of the affected men were with abnormal sperm concentration and/or motility with an indefinite genotype-phenotype relationship. As for PGT, the fertilization rate of couples with the male partner having ADPKD was relatively lower compared to those with the female partner being affected. The ADPKD patients receiving PGT usually achieved high rates of live births. These findings expanded the variant spectrum of PKD genes and emphasized the application prospect of blocker displacement amplification on PKD1-related genetic diagnosis.

Mutation Analysis of Autosomal-Dominant Polycystic Kidney Disease Patients

Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by bilateral kidney cysts that ultimately lead to end-stage kidney disease. While the major causative genes of ADPKD are PKD1 and PKD2, other genes are also thought to be involved. Fifty ADPKD patients were analyzed by exome sequencing or multiplex ligation-dependent probe amplification (MLPA), followed by long polymerase chain reaction and Sanger sequencing. Variants in PKD1 or PKD2 or GANAB were detected in 35 patients (70%). Exome sequencing identified 24, 7, and 1 variants in PKD1, PKD2, and GANAB, respectively, in 30 patients. MLPA analyses identified large deletions in PKD1 in three patients and PKD2 in two patients. We searched 90 cyst-associated genes in 15 patients who were negative by exome sequencing and MLPA analyses, and identified 17 rare variants. Four of them were considered "likely pathogenic" or "pathogenic" variants according to the American College of Medical Genetics and Genomics guidelines. Of the 11 patients without a family history, four, two, and four variants were found in PKD1, PKD2, and other genes, respectively, while no causative gene was identified in one patient. While the pathogenicity of each variant in these genes should be carefully assessed, a comprehensive genetic analysis may be useful in cases of atypical ADPKD.

Acute renal intracystic hemorrhage in patients with autosomal dominant polycystic kidney disease.

Renal cyst bleeding is a frequent problem in patients with autosomal dominant polycystic kidney disease (ADPKD). However, information is still limitedon its frequency, causative factors, and effects on enlargement of polycystic kidneys in ADPKD. We investigated the total volume of acute renal intracystic hemorrhage and its association with total kidney volume (TKV) in a large seriesofpatients with ADPKD on dialysis, referred forrenal transcatheter arterial embolization. All patients had undergone CT scan and MRI scan before the procedure.We evaluated factors potentially associated with acute renal intracystic hemorrhage.The association between thevolume of acute renal intracystic hemorrhage and the potential predisposing and associated factors was analysed by univariable and multivariable regressions. RESULTS: We enrolled 199 patients who underwent renal transcatheter arterial embolization from 2014 to 2018 (107 men, 92 women; mean age 59.1 ± 8.6years). The median volume of acute renal intracystic hemorrhage was 97.3ml (interquartile range 36.6-261.7ml). Multivariable analysis revealed that body weight, kidney stones, systolic blood pressure, and total volume of acute renal intracystic hemorrhage were significantly associated with TKV; age, body mass index, smoking, renal cyst infection, serum alkaline phosphatase, and TKV were significantly associated withthe volume ofacute renal intracystic hemorrhage ; and sex, age, dialysis vintage, TKV, and total volume of acute renal intracystic hemorrhage were significantly associated with the number of microcoils required to achieve renal transcatheter arterial embolization. Total volume of acute renal intracystic hemorrhage was significantly associated with TKV(r = 0.15, p = 0.0325)and wasgreater inyounger patients (r= - 0.32, p < 0.0001). Total volume of acute renal intracystic hemorrhagewas also correlated with the number ofmicrocoils required for renal transcatheter arterial embolization(r = 0.23, p = 0.0012). Acute renal intracystic hemorrhage is frequent among ADPKD patients on dialysis, and total volume of acute renal intracystic hemorrhage significantly associated with TKV.Total volume of acute renal intracystic hemorrhage was greater in younger patients with higher renal artery luminal size. These results suggest that renal cyst bleeding and renal artery blood flow may synergistically accelerate the enlargement of polycystic kidneysin ADPKDpatients on dialysis.

The Clinical and Mutational Spectrum of 69 Turkish Children with Autosomal Recessive or Autosomal Dominant Polycystic Kidney Disease: A Multicenter Retrospective Cohort Study

Introduction: Autosomal recessive polycystic kidney disease (ARPKD) is associated with pathogenic variants in the PKHD1 gene. Autosomal dominant polycystic kidney disease (ADPKD) is mainly associated with pathogenic variants in PKD1 or PKD2. The present study aimed to identify the clinical and genetic features of Turkish pediatric ARPKD and ADPKD patients. Methods: This multicenter, retrospective cohort study included 21 genetically confirmed ARPKD and 48 genetically confirmed ADPKD patients from 7 pediatric nephrology centers. Demographic features, clinical, and laboratory findings at presentation and during 12-month intervals were recorded. Results: The median age of the ARPKD patients at diagnosis was lower than the median age of ADPKD patients (10.5 months [range: 0–15 years] vs. 5.2 years [range: 0.1–16 years], respectively, [p = 0.014]). At the time of diagnosis, the median eGFR in the ARPKD patients was lower compared to that of ADPKD patients (81.6 [IQR: 28.7–110.5] mL/min/1.73 m2 and 118 [IQR: 91.2–139.8] mL/min/1.73 m2, respectively, [p = 0.0001]). In total, 11 (52.4%) ARPKD patients had malnutrition; 7 (33.3%) patients had growth retardation at presentation; and 4 (19%) patients had both malnutrition and growth retardation. At diagnosis, 8 (16.7%) of the ADPKD patients had malnutrition, and 5 (10.4%) patients had growth retardation. The malnutrition, growth retardation, and hypertension rates at diagnosis were higher in the ARPKD patients than the ADPKD patients (p = 0.002, p = 0.02, and p = 0.0001, respectively). ARPKD patients with malnutrition and growth retardation had worse renal survival compared to the patients without (p = 0.03 and p = 0.01). Similarly, ADPKD patients with malnutrition had worse renal survival compared to the patients without (p = 0.002). ARPKD patients with truncating variants had poorer 3- and 6-year renal outcome than those carrying non-truncating variants (p = 0.017). Conclusion: Based on renal survival analysis, type of genetic variant, growth retardation, and/or malnutrition at presentation were observed to be factors associated with progression to chronic kidney disease (CKD). Differentiation of ARPKD and ADPKD, and identification of the predictors of the development of CKD are vital for optimal management of patients with ARPKD or ADPKD.

Effect of Averaging Measurements From Multiple MRI Pulse Sequences on Kidney Volume Reproducibility in Autosomal Dominant Polycystic Kidney Disease.

Total kidney volume (TKV) is an important biomarker for assessing kidney function, especially for autosomal dominant polycystic kidney disease (ADPKD). However, TKV measurements from a single MRI pulse sequence have limited reproducibility, ± ~5%, similar to ADPKD annual kidney growth rates. To improve TKV measurement reproducibility on MRI by extending artificial intelligence algorithms to automatically segment kidneys on T1-weighted, T2-weighted, and steady state free precession (SSFP) sequences in axial and coronal planes and averaging measurements. Retrospective training, prospective testing. Three hundred ninety-seven patients (356 with ADPKD, 41 without), 75% for training and 25% for validation, 40 ADPKD patients for testing and 17 ADPKD patients for assessing reproducibility. T2-weighted single-shot fast spin echo (T2), SSFP, and T1-weighted 3D spoiled gradient echo (T1) at 1.5 and 3T. 2D U-net segmentation algorithm was trained on images from all sequences. Five observers independently measured each kidney volume manually on axial T2 and using model-assisted segmentations on all sequences and image plane orientations for two MRI exams in two sessions separated by 1-3 weeks to assess reproducibility. Manual and model-assisted segmentation times were recorded. Bland-Altman, Schapiro-Wilk (normality assessment), Pearson's chi-squared (categorical variables); Dice similarity coefficient, interclass correlation coefficient, and concordance correlation coefficient for analyzing TKV reproducibility. P-value < 0.05 was considered statistically significant. In 17 ADPKD subjects, model-assisted segmentations of axial T2 images were significantly faster than manual segmentations (2:49 minute vs. 11:34 minute), with no significant absolute percent difference in TKV (5.9% vs. 5.3%, P=0.88) between scans 1 and 2. Absolute percent differences between the two scans for model-assisted segmentations on other sequences were 5.5% (axial T1), 4.5% (axial SSFP), 4.1% (coronal SSFP), and 3.2% (coronal T2). Averaging measurements from all five model-assisted segmentations significantly reduced absolute percent difference to 2.5%, further improving to 2.1% after excluding an outlier. Measuring TKV on multiple MRI pulse sequences in coronal and axial planes is practical with deep learning model-assisted segmentations and can improve TKV measurement reproducibility more than 2-fold in ADPKD. 2 TECHNICAL EFFICACY: Stage 1.