Autosomal Dominant Polycystic Kidney Disease Patients Research Articles

Autosomal Dominant Polycystic Kidney Disease: Clinical Assessment of Rapid Progression

Background: Autosomal dominant polycystic kidney disease (ADPKD) causes the development of renal cysts and leads to a decline in renal function. Limited guidance exists in clinical practice on the use of tolvaptan. A decision algorithm from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Working Groups of Inherited Kidney Disorders and European Renal Best Practice (WGIKD/ERBP) has been proposed to identify candidates for tolvaptan treatment; however, this algorithm has not been assessed in clinical practice. Methods: Eighteen-month cross-sectional, unicenter, observational study assessing 305 consecutive ADPKD patients. The ERA-EDTA WGIKD/ERBP algorithm with a stepwise approach was used to assess rapid progression (RP). Subsequently, expanded criteria based on the REPRISE trial were applied to evaluate the ­impact of extended age (≤55 years) and estimated glomerular filtration rate (eGFR; ≥25 mL/min/1.73 m²). Results: Historical eGFR decline, indicative of RP, was fulfilled in 26% of 73 patients who were candidates for RP assessment, mostly aged 31–55 years. Further tests including ultrasound and MRI measurements of kidney volume plus genetic testing enabled the evaluation of the remaining patients. Overall, 15.7% of patients met the criteria for rapid or likely RP using the algorithm, and the percentage increased to 27% when extending age and eGFR. Conclusions: The ERA-EDTA WGIKD/ERBP algorithm provides a valuable means of identifying in routine clinical practice patients who may be eligible for treatment with tolvaptan. The impact of a new threshold for age and eGFR may increase the percentage of patients to be treated.

Cyst infection in autosomal dominant polycystic kidney disease: penetration of meropenem into infected cysts

BackgroundCyst infection is a common and serious complication of autosomal dominant polycystic kidney disease (ADPKD) that is often refractory. Carbapenems are frequently needed to treat to patients with refractory cyst infection, but little is known about the penetration of newer water-soluble carbapenems into cysts. This study investigated the penetration of meropenem (MEPM) into infected cysts in patients with ADPKD.MethodsBetween August 2013 and January 2014, 10 ADPKD patients (14 infected cysts) receiving MEPM at Toranomon Hospital underwent drainage of infected cysts and definite cyst infection was confirmed through detection of neutrophils by cyst fluid analysis. The serum concentration of MEPM was measured just after intravenous administration and was compared with that in fluid aspirated from infected cysts.ResultsIn the patients undergoing cyst drainage, the mean serum MEPM concentration was 35.2 ± 12.2 μg/mL (range: 19.7 to 59.2 μg/mL, while the mean cyst fluid concentration of MEPM in the drained liver cysts (n = 12) or kidney cysts (n = 2) was 3.03 ± 2.6 μg/mL (range: 0 to 7.3 μg/mL). In addition, the mean cyst fluid/serum MEPM concentration ratio was 9.46 ± 7.19% (range: 0 to 18.8%). There was no relationship between the cyst fluid concentration of MEPM and the time until drainage after MEPM administration or between the cyst fluid/serum MEPM concentration ratio and the time until drainage.ConclusionThese findings suggest that MEPM shows poor penetration into infected cysts in ADPKD patients.Trial registrationThis study was registered with the University Hospital Medical Information Network (UMIN) as “Penetration of meropenem into cysts in patients with autosomal dominant polycystic kidney disease (ADPKD)”, UMIN ID 000011292 on July 26th, 2013.

NHA2 promotes cyst development in an invitro model of polycystic kidney disease.

Significant and selective up-regulation of the Na+ /H+ exchanger NHA2 (SLC9B2) was observed in cysts of patients with autosomal dominant polycystic kidney disease. Using the MDCK cell model of cystogenesis, it was found that NHA2 increases cyst size. Silencing or pharmacological inhibition of NHA2 inhibits cyst formation invitro. Polycystin-1 represses NHA2 expression via Ca2+ /NFAT signalling whereas the dominant negative membrane-anchored C-terminal fragment (PC1-MAT) increased NHA2 levels. Drugs (caffeine, theophylline) and hormones (vasopressin, aldosterone) known to exacerbate cysts elicit NHA2 expression. Taken together, the findings reveal NHA2 as a potential new player in salt and water homeostasis in the kidney and in the pathogenesis of polycystic kidney disease. Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2 encoding polycystin-1 (PC1) and polycystin-2 (PC2), respectively. The molecular pathways linking polycystins to cyst development in ADPKD are still unclear. Intracystic fluid secretion via ion transporters and channels plays a crucial role in cyst expansion in ADPKD. Unexpectedly, we observed significant and selective up-regulation of NHA2, a member of the SLC9B family of Na+ /H+ exchangers, that correlated with cyst size and disease severity in ADPKD patients. Using three-dimensional cultures of MDCK cells to model cystogenesis invitro, we showed that ectopic expression of NHA2 is causal to increased cyst size. Induction of PC1 in MDCK cells inhibited NHA2 expression with concordant inhibition of Ca2+ influx through store-dependent and -independent pathways, whereas reciprocal activation of Ca2+ influx by the dominant negative membrane-anchored C-terminal tail fragment of PC1 elevated NHA2. We showed that NHA2 is a target of Ca2+ /NFAT signalling and is transcriptionally induced by methylxanthine drugs such as caffeine and theophylline, which are contraindicated in ADPKD patients. Finally, we observed robust induction of NHA2 by vasopressin, which is physiologically consistent with increased levels of circulating vasopressin and up-regulation of vasopressin V2 receptors in ADPKD. Our findings have mechanistic implications on the emerging use of vasopressin V2 receptor antagonists such as tolvaptan as safe and effective therapy for polycystic kidney disease and reveal a potential new regulator of transepithelial salt and water transport in the kidney.

Incremental health care resource utilization and expenditures associated with autosomal dominant polycystic kidney disease

PurposeIncremental health care resource utilization and expenditures associated with autosomal dominant polycystic kidney disease (ADPKD) were estimated.MethodsStudy data were from a large administrative claims database. Individuals aged 18 years or older enrolled in tracked health plans for 12 months from April 1, 2011 through March 31, 2012, and with an International Classification of Disease, Ninth Revision, Clinical Modification diagnosis code for “polycystic kidney, autosomal dominant” (753.13) or for “polycystic kidney, unspecified type” (753.12) were identified as having ADPKD, and linked one-to-one with individuals without ADPKD based on age and gender. Zero-inflated negative binomial models estimated incremental health care resource utilization and expenditures, adjusting for risk factors.ResultsA total of 3,844 individuals with ADPKD who satisfied selection criteria were linked one-to-one with 3,844 individuals without ADPKD. Multivariate, regression models adjusting for risk factors revealed incremental mean (standard error) resource use associated with ADPKD of 0.68 (0.090) hospital days, equal to 68 additional hospital days per 100 ADPKD patients, and 6.9 (0.28) outpatient visits, equal to 690 additional visits per 100 ADPKD patients. Mean (standard error) incremental total expenditures associated with ADPKD were US$8,639 ($470). Mean incremental expenditures were largest for outpatient expenditures at US$4,918 ($198), followed by mean incremental hospital expenditures of US$2,603 ($263), and mean incremental medication expenditures of US$1,589 ($77). Based on sub-group analysis, mean incremental total expenditures were US$2,944 ($417) among ADPKD patients without end-stage renal disease and US$38,962 ($6,181) for those with end-stage renal disease.ConclusionADPKD was associated with considerable incremental health care resource utilization and expenditures. Significant illness burden was found even before patients reached end-stage renal disease.

PUK18 - Insights in Newly Diagnosed Autosomal Dominant Polycystic Kidney Disease (ADPKD) Patient Characteristics Using German Claims Data

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease worldwide and a significant burden to patients and societies across Europe. In the light of recent treatment advances, the need to expand the sparse knowledge about patient pathways in ADPKD has increased. As a first step the objective of this retrospective database analysis was to provide real-world data on the health care specialists (HCS) performing the initial ADPKD diagnosis. Healthcare claims data from a German sickness funds database with data on approximately 3 million patients were analyzed. Adult patients newly diagnosed with ADPKD were included - ICD-10 GM Q61.2 or Q61.3 in at least one outpatient or inpatient coding. Baseline period was defined as 12 months prior to the index diagnosis. For evaluation of baseline comorbidity a comparison group was created from a 1:50 random match. We found 1,185 newly adult patients diagnosed with ADPKD between 2012 and 2016. The mean patient age is 64 years with slightly more male patients (56%). The baseline comorbidities are generally comparable to the control group, although ADPKD patients have higher ratios of renal disease (excluding Q61.2/3) and metastatic solid tumor and lower dementia rates. Most patients (N=939, 79.2%) have no code for Chronic Kidney Disease (CKD) stage at ADPKD index diagnosis, while the remainder is mostly (N=127, 10.7%) at CDK stage 3. Most patients receive their ADPKD diagnosis in an outpatient care setting from a general practitioner (GP) or one of the related specialist fields such as urology (19%), nephrology (14%), and radiology (8%). Presumably, there is also an accumulation of incidental findings in other areas such as hospital, surgery, gastroenterology and gynecology. In this retrospective study we derived the main HCSs diagnosing ADPKD. Most patients are diagnosed at a GP or related specialist, but incidental findings do occur.

Abstract 124: Nadph Oxidase 4 and Mitochondrial Abnormalities Contribute to Oxidative Stress and Endothelial Dysfunction in Young Normotensive Patients With Autosomal Dominant Polycystic Kidney Disease

Background: Fifty percent of patients with autosomal dominant polycystic kidney disease (ADPKD) present hypertension (HTN) early on, which increases to nearly 100% at end-stage, and is associated with faster renal functional decline. Endothelial dysfunction (ED) accompanied by oxidative stress (OS) precedes the development of HTN, but the mechanisms responsible remain unknown. The aim of this study was to determine whether NADPH oxidase (NOX4) and mitochondrial dysfunction contribute to OS and ED preceding HTN in early ADPKD. Methods: We prospectively measured plasma levels of homocysteine (Hcy), 8-isoprostane, NOX4 and the mtDNA genes COX3 and ND1 in young normotensive (without BP medication) ADPKD patients, and age-matched healthy volunteers (HV) (n=10, each). Total kidney volume (TKV) and Renal Blood Flow (RBF) were evaluated by MRI. Results: BP levels were higher in ADPKD, and HtTKV was twofold higher in ADPKD vs. controls. eGFR and RBF were similar between the groups (Table). Plasma Hcy, 8-isoprostanes and NOX4 were higher in ADPKD, and correlated directly with HtTKV (p<0.05, Figure), but the correlation with RBF was not significant. Plasma mtDNA copy number were lower in ADPKD compared to controls, and correlated inversely with HtTKV(R 2 0.397 and 0.392 respectively). Conclusion: Early ADPKD is associated with elevation in Hcy, 8-isoprostane, and NOX4 levels, and decreased mtDNA copy numbers, which precede the reduction in RBF and the development of HTN, and are associated with disease severity. NOX4 and mitochondrial abnormalities may contribute to oxidative stress, endothelial dysfunction, and possibly the development of HTN and disease progression in ADPKD.

The association between autosomal dominant polycystic kidney disease and cancer.

Autosomal dominant polycystic kidney disease (ADPKD) is considered as a tumor-like disease because there are many biological similarities between ADPKD and cancer. However, the commonalities between them are provocative, particularly under the conditions of recent clinical studies. In this paper, we review clinical studies about the association between cancer and ADPKD, and compare the biological characteristics between them, with focusing on cell proliferation, differentiation, migration, apoptosis, and polarity. With detailed literature reviewing, we believe that ADPKD patients have a higher risk of tumorigenesis and thus highly recommend being aware of tumorigenesis during follow-up in patients with ADPKD.

The association of endothelin-1 levels with renal survival in polycystic kidney disease patients

The prominent features of autosomal dominant polycystic kidney disease (ADPKD) are early development of hypertension, chronic kidney disease and cardiovascular problems. Thus, we aimed to investigate the role of endothelin, a vascular biomarker, in the clinical course of ADPKD, including renal and cardiovascular survival. In 138 patients with ADPKD and 28 healthy controls, we measured serum endothelin-1 (ET-1) levels by enzyme-linked immunosorbent assay (ELISA). Endothelium-dependent vasodilatation (flow-mediated dilatation, FMD) and endothelium-independent vasodilatation (nitroglycerin-mediated dilatation, NMD) of the brachial artery were assessed non-invasively with high-resolution ultrasound. Magnetic resonance imaging (MRI) was performed with a 1.5-T system, and total kidney volumes were calculated using mid-slice technique. To determine PKD1 and PKD2 genotype, we performed molecular and genetic tests involving the following steps: DNA isolation, next-generation sequencing (NGS) and data analysis. Endothelin levels and height-adjusted total kidney volumes (hTKV) significantly increased while the estimated glomerular filtration rate (eGFR) decreased across CKD stages 1-4. Hypertension was more frequent in ADPKD patients with high serum endothelin. At multivariate Cox analysis, endothelin level, PKD1 truncating mutation, hTKV, high-sensitive C reactive protein (hs-CRP) level and the presence of diabetes mellitus were associated with the risk of overall survival. Moreover, endothelin level, PKD1 truncating mutation, hTKV, age and presence of hypertension were associated with the risk of renal survival. Additionally, body mass index (BMI), FMD, PKD1 truncating mutation, endothelin and triglyceride levels were independently associated with hypertension. Increased serum endothelin levels independently predict hypertension in ADPKD. Serum endothelin levels are also associated with both renal and overall survival in patients with ADPKD.

Pretransplant Nephrectomy for Large Polycystic Kidneys in ADPKD (Autosomal Dominant Polycystic Kidney Disease) Patients

Introduction and Background Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by relentless development and growth of cysts causing progressive kidney enlargement and progressive renal failure. Diuresis and fluid volume control is often preserved also during the dialytic period. Some recent studies have proposed peritoneal dialysis (PD) as a valid alternative even for ADPKD, which was once considered a relative contraindication because of the possible limited intraperitoneal space and the risk of hernia. Native kidneys are not routinely removed before transplantation in consideration of the significant morbidity and mortality associated to the procedure. Indications for nephrectomy include recurrent or severe infection, symptomatic nephrolithiasis, recurrent or severe bleeding, intractable pain, suspicion of renal cancer and space restrictions prior to transplantation. Considering that after a trans-peritoneal nephrectomy the peritoneum often results damaged and unsuitable for PD, the aim of this study is to assess if and how long after nephrectomy PD may be effectively resumed. Materials and Method A retrospective analysis of ADPKD patients in waiting list for kidney transplant which underwent nephrectomy in our trasplant surgery department between December 2012 and October 2017 was carried out. All patients were included, male and female, and the indications for nephrectomy were symptoms (pain, urinary tract infections or hematuria) or steric hindrance. In all cases the surgical procedure was performed with meticoulus technique by laparotomic access with subcostal incision with recostruction of the posterior peritoneal flap in order to preserve peritoneal cavity avoiding visceral adhesions and for future peritoneal dialysis recovery. Results and Discussion From December 2012 to October 2017 30 ADPKD patients underwent nephrectomy in our transplant surgery department. The patients were 18 (63%) males and 12 (37%) females, with a mean age of 54±8. 9 patients were in peritoneal dialysis, 19 in hemodialysis and 2 were affected by stage 5 chronic renal failure. 4 patients underwent nephrectomy after trasplantation. The indication for nephrectomy was steric hindrance in 43,3% of cases, while 56,6% of patients had symptoms (52,9% UTI, 35,3% haematuria and 11,7% pain). No complications were reported after surgery. Among patients treated with peritoneal dialysis before nephrectomy 3 underwent nephrectomy after trasplantation, 3 started hemodialysis and 3 resumed peritoneal dialysis 30 days after surgery. Conclusions Monolateral nephrectomy with a laparotomic approach seems to be a safe and feasible procedure also for very large kidneys. A meticulous technique with accurate peritoneal preservation avoids commons postsurgical complications and may allow a rapid peritoneal dialysis resume.

EPICARDIAL FAT THICKNESS IN PATIENTS WITH AUTOSOMAL DOMINANT POLYCISTIC KIDNEY DISEASE

Objective: Autosomal dominant polycystic kidney disease (ADPKD) is associated with early organ damage such as left ventricular hypertrophy (LVH) and higher cardiovascular risk when compared to essential hypertension (EH). Epicardial adipose tissue (EAT) is a new cardiovascular risk factor, but its correlation with LVH in ADPKD is unknown. We sought to evaluate the correlation of ultrasound measured EAT and LVH in a well-studied group of hypertensive patients with ADPKD in comparison with essential hypertension (EH) subjects. Design and method: We performed ultrasound measurement of the EAT and other echocardiographic parameters, such as left ventricular mass (LVM), left ventricular mass indexed by body surface area (LVMi), and left atrium size in 41 consecutive hypertensive patients with ADPKD, compared to 89 EH patients. Results: EAT was significantly higher in ADPKD group respect to EH subjects (9.2 ± 2.9 mm vs 7.8 ± 1.6 mm, p < 0.001), and significantly correlated with LVM, LVMi and left atrium size in the ADPKD group (r = 0.56, p = 0.005; r = 0.424, p = 0.022; and r = 0.48, p = < 0.001, respectively). Comparing EAT against body mass index (BMI), waist circumference (WC), systolic blood pressure (SBP), diastolic blood pressure (DBP) and age, we found that EAT is the strongest predictor of LVMi (B = 0.59, p = 0.036). Conclusions: Our data shows that EAT is higher in ADPKD patients than in EH subjects and independently correlates with LVMi. EAT measurement can be as useful marker in the cardiovascular risk stratification in ADPKD.

Long noncoding RNA Hoxb3os is dysregulated in autosomal dominant polycystic kidney disease and regulates mTOR signaling

Autosomal dominant polycystic kidney disease (ADPKD) is a debilitating disease that is characterized by the accumulation of numerous fluid-filled cysts in the kidney. ADPKD is primarily caused by mutations in two genes, PKD1 and PKD2 Long noncoding RNAs (lncRNA), defined by a length >200 nucleotides and absence of a long ORF, have recently emerged as epigenetic regulators of development and disease; however, their involvement in PKD has not been explored previously. Here, we performed deep RNA-Seq to identify lncRNAs that are dysregulated in two orthologous mouse models of ADPKD (kidney-specific Pkd1 and Pkd2 mutant mice). We identified a kidney-specific, evolutionarily conserved lncRNA called Hoxb3os that was down-regulated in cystic kidneys from Pkd1 and Pkd2 mutant mice. The human ortholog HOXB3-AS1 was down-regulated in cystic kidneys from ADPKD patients. Hoxb3os was highly expressed in renal tubules in adult WT mice, whereas its expression was lost in the cyst epithelium of mutant mice. To investigate the function of Hoxb3os, we utilized CRISPR/Cas9 to knock out its expression in mIMCD3 cells. Deletion of Hoxb3os resulted in increased phosphorylation of mTOR and its downstream targets, including p70 S6 kinase, ribosomal protein S6, and the translation repressor 4E-BP1. Consistent with activation of mTORC1 signaling, Hoxb3os mutant cells displayed increased mitochondrial respiration. The Hoxb3os mutant phenotype was partially rescued upon re-expression of Hoxb3os in knockout cells. These findings identify Hoxb3os as a novel lncRNA that is down-regulated in ADPKD and regulates mTOR signaling and mitochondrial respiration.

LEVELS OF ENDOCAN, ANGIOPOIETIN-2 AND HIF-1A IN PATIENTS WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE AND DIFFERENT LEVELS OF RENAL FUNCTION

Objective: Endothelial dysfunction leading to unbalanced vasoconstriction and ischemia of renal parenchyma is increasingly proposed as an additional pathway of renal damage in autosomal-dominant-polycystic-kidney-disease (ADPKD). However, human studies investigating the evolution of such phenomena are limited. This study investigated the levels of emerging biomarkers of endothelial function, angiogenesis and hypoxia, in ADPKD patients with different renal function. Design and method: The study population consisted of three groups: 26 ADPKD patients with impaired renal function (Group A) (eGFR 45–70 ml/min/1.73m2), 26 ADPKD patients with preserved renal function (Group B) (eGFR>70 ml/min/1.73m2), and 26 age- and sex- matched controls with no history of renal disease. Circulating levels of endocan (endothelial cell-specific molecule-1) angiopoietin-2, and hypoxia-induced-factor-1a (HIF-1a) were determined by ELISA techniques. Results: Patients in Group A had significantly higher levels of endocan (7.17 ± 0.43 ng/ml), angiopoietin-2 (5,595.43 ± 3,390) and HIF-1a (163.68 ± 37.84 pg/ml) compared to patients in Group B (6.86 ± 0.59 ng/ml, p = 0.017, 3,854.41 ± 3,014.30, p = 0.018, 136.84 ± 42.10 pg/ml, p = 0.019, respectively) or controls (4.83 ± 0.69 ng/ml, 1,069 ± 427.88 pg/ml, 70.20 ± 17.49 pg/ml, p < 0.001 for all comparisons). Of note, patients in Group B had also higher levels of all markers compared to controls (p < 0.001), despite having similar renal function. In correlation analyses within ADPKD patients, we noted strong correlations of all studied markers with ADMA (endocan r = 0.908, p < 0.001, angiopoietin2 r = 0.983, p < 0.001 and HIF-1a r = 0.998, p < 0.001), and only weak or modest correlations with eGFR. Conclusions: In conclusion, this study suggests that not only patients with low eGFR, but also those at early stages of the ADPKD had higher expression of markers indicative for endothelial dysfunction, angiogenesis and hypoxia in comparison to controls. These results could lead to the hypothesis that local microcirculatory changes may come early in the course of ADPKD and could be a cause rather than a result of disease progression and eGFR decline.

Effect of Sirolimus on Native Total Kidney Volume After Transplantation in Patients with Autosomal Dominant Polycystic Kidney Disease: A Randomized Controlled Pilot Study

BackgroundThe mammalian target of rapamycin (mTOR) pathway has been shown to be central to cyst formation and growth in patients with autosomal dominant polycystic kidney disease (ADPKD). Drugs that suppress mTOR signaling are frequently used as antiproliferative agents for maintenance immunosuppression in patients who have undergone kidney transplantation. The aim of this study was to determine the effect of sirolimus, an mTOR inhibitor, on cyst volume regression in patients with ADPKD who have undergone renal transplantation. MethodsIn this single-center, prospective, open-label, parallel-group, randomized trial, 23 adult patients with ADPKD who successfully underwent renal transplantation from 2008 to 2012 were subsequently randomized (on a 1:1 basis) to a maintenance immunosuppression regimen with either sirolimus (sirolimus, tacrolimus, prednisone) or mycophenolate (mycophenolate, tacrolimus, prednisone). Total kidney volumes were measured by means of high-resolution magnetic resonance imaging within 2 weeks after transplantation and at 1 year. The primary end point was change in total kidney volume at 1 year. ResultsSixteen patients completed the 1-year study (8 patients in each group). There was a decrease in kidney volume in both the sirolimus group (percentage change from baseline, 20.5%; P < .001) and mycophenolate group (percentage change from baseline, 17%; P = .048), but there was no significant difference in percentage change of total kidney volume between the groups (P = .665). ConclusionsIn ADPKD patients at 1 year after kidney transplantation, there was a similar decrease in polycystic kidney volume in patients receiving an immunosuppression regimen containing sirolimus compared with patients receiving mycophenolate.

Polycystin-1 dysfunction impairs electrolyte and water handling in a renal precystic mouse model for ADPKD.

The PKD1 gene encodes polycystin-1 (PC1), a mechanosensor triggering intracellular responses upon urinary flow sensing in kidney tubular cells. Mutations in PKD1 lead to autosomal dominant polycystic kidney disease (ADPKD). The involvement of PC1 in renal electrolyte handling remains unknown since renal electrolyte physiology in ADPKD patients has only been characterized in cystic ADPKD. We thus studied the renal electrolyte handling in inducible kidney-specific Pkd1 knockout (iKsp- Pkd1-/-) mice manifesting a precystic phenotype. Serum and urinary electrolyte determinations indicated that iKsp- Pkd1-/- mice display reduced serum levels of magnesium (Mg2+), calcium (Ca2+), sodium (Na+), and phosphate (Pi) compared with control ( Pkd1+/+) mice and renal Mg2+, Ca2+, and Pi wasting. In agreement with these electrolyte disturbances, downregulation of key genes for electrolyte reabsorption in the thick ascending limb of Henle's loop (TA;, Cldn16, Kcnj1, and Slc12a1), distal convoluted tubule (DCT; Trpm6 and Slc12a3) and connecting tubule (CNT; Calb1, Slc8a1, and Atp2b4) was observed in kidneys of iKsp- Pkd1-/- mice compared with controls. Similarly, decreased renal gene expression of markers for TAL ( Umod) and DCT ( Pvalb) was observed in iKsp- Pkd1-/- mice. Conversely, mRNA expression levels in kidney of genes encoding solute and water transporters in the proximal tubule ( Abcg2 and Slc34a1) and collecting duct ( Aqp2, Scnn1a, and Scnn1b) remained comparable between control and iKsp- Pkd1-/- mice, although a water reabsorption defect was observed in iKsp- Pkd1-/- mice. In conclusion, our data indicate that PC1 is involved in renal Mg2+, Ca2+, and water handling and its dysfunction, resulting in a systemic electrolyte imbalance characterized by low serum electrolyte concentrations.

Quantification of Urinary Protein Biomarkers of Autosomal Dominant Polycystic Kidney Disease by Parallel Reaction Monitoring.

Autosomal dominant polycystic kidney disease (ADPKD) is a life-long disease in which the genes responsible are known, but the pathogenesis of cyst formation and cyst growth are not understood. Cyst growth ultimately leads to end-stage renal failure in most patients. Analysis of the urinary proteome offers the potential to identify proteins that indicate the presence of cysts (and thus provides diagnosis) as well as the rates of cyst growth (providing prognostic information). A scheduled parallel reaction monitoring (sPRM) assay is performed on urine samples from 14 patients and 18 normal controls. For relative quantification, stable isotope-labeled synthetic peptides are spiked in the urinary protein digests prior to data collection. The data are subsequently normalized to creatinine and protein concentration in the respective urine samples to control for variations in water intake between individuals. Out of the 143 urinary proteins targeted for sPRM assay, 69 proteins are observed to be significantly dysregulated in ADPKD. The dysregulated proteins are used to cluster ADPKD patients into those who are more or less similar to normal controls. This study shows that sPRM is a promising approach to rapidly screen large numbers of proteins in urine in order to provide earlier diagnosis and potentially better understand the pathogenesis of ADPKD development and progression.

The association of serum angiogenic growth factors with renal structure and function in patients with adult autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is a common congenital chronic kidney disease (CKD). We report here the relationship of serum angiopoietin-1 (Ang-1), Ang-2, and vascular endothelial growth factor (VEGF) with total kidney volume (TKV), total cyst volume (TCV), and renal failure in adult ADPKD patients at various stages of CKD. This cross-sectional study was conducted with 50 patients diagnosed with ADPKD and a control group of 45 age-matched healthy volunteers. In patient group, TKV and TCV were determined with upper abdominal magnetic resonance imaging, whereas in controls, TKV was determined with ultrasonography according to ellipsoid formula. Renal function was assessed with serum creatinine, estimated glomerular filtration rate (eGFR), and spot urinary protein/creatinine ratio (UPCR). Ang-1, Ang-2, and VEGF were measured using enzyme-linked immunosorbent assay. Patients with ADPKD had significantly higher TKV (p < 0.001) and UPCR (p < 0.001), and lower eGFR (p ≤ 0.001) compared to the controls. Log10Ang-2 was found to be higher in ADPKD patients at all CKD stages. Multiple linear regression analysis showed that there was no association between log10Ang-1, log10Ang-2, or log10VEGF and creatinine, eGFR, UPCR, log10TKV (p > 0.05). There was no association of serum angiogenic growth factors with TKV or renal failure in ADPKD patients. Increased serum Ang-2 observed in stages 1-2 CKD suggests that angiogenesis plays a role in the progression of early stage ADPKD, but not at later stages of the disease. This may be explained by possible cessation of angiogenesis in advanced stages of CKD due to the increased number of sclerotic glomeruli.

Levels of Endocan, Angiopoietin-2, and Hypoxia-Inducible Factor-1a in Patients with Autosomal Dominant Polycystic Kidney Disease and Different Levels of Renal Function

Background: Endothelial dysfunction leading to unbalanced vasoconstriction and ischemia of renal parenchyma is increasingly proposed as an alternative pathway of renal damage in autosomal dominant polycystic kidney disease (ADPKD). However, human studies investigating the evolution of such phenomena are limited. This study investigated the levels of emerging biomarkers of endothelial function, angiogenesis and hypoxia, in ADPKD patients with different renal function. Methods: The study population consisted of three groups: 26 ADPKD patients with impaired renal function (Group A; estimated glomerular filtration rate [eGFR] 45–70 mL/min/1.73 m²), 26 ADPKD patients with preserved renal function (Group B; eGFR >70 mL/min/1.73 m²), and 26 age- and sex-matched controls with no history of renal disease. Circulating levels of endocan (endothelial cell-specific molecule-1) angiopoietin-2, and hypoxia-inducible factor-1a (HIF-1a) were determined by enzyme-linked immunosorbent assay techniques. Results: Patients in Group A had significantly higher levels of endocan (7.17 ± 0.43 ng/mL), angiopoietin-2 (5,595.43 ± 3,390), and HIF-1a (163.68 ± 37.84 pg/mL) compared to patients in Group B (6.86 ± 0.59 ng/mL, p = 0.017, 3,854.41 ± 3,014.30, p = 0.018, 136.84 ± 42.10 pg/mL, p = 0.019 respectively) or controls (4.83 ± 0.69 ng/mL, 1,069 ± 427.88 pg/mL, 70.20 ± 17.49 pg/mL, p < 0.001 for all comparisons). Of note, patients in Group B had also higher levels of all markers compared to controls (p < 0.001) despite having similar renal function. In correlation analyses within ADPKD patients, we noted strong correlations of all studied markers with asymmetric dimethylarginine (ADMA; endocan r = 0.908, p < 0.001, angiopoietin-2 r = 0.983, p < 0.001 and HIF-1a r = 0.998, p < 0.001), and only weak or modest correlations with eGFR. Conclusions: This study suggests that endothelial dysfunction causing microcirculatory changes, linked to angiogenesis and hypoxia, may come early in the course of ADPKD and could be a key regulator of renal injury progression.

Increased risk of aortic root aneurism in patient with autosomal dominant polycystic kidney disease

Recently, simple renal cysts have been linked to an increased risk of aortic aneurism. In autosomal dominant polycystic kidney disease (ADPKD), there is a higher prevalence of intracranial aneurisms but little evidence regarding aortic dilation. The aim of this study was to compare aortic root and ascending aorta diameters in ADPKD patients and matched controls. From 2008 to 2016, 61 consecutive ADPKD patients who had an echocardiography in our institution were matched 1:1 with controls non-ADPKD patients for sex, age, blood pressure (BP) and beta-blocker therapy. Paired- t tests were used for quantitative variables and McNemar tests for qualitative variables. Mean age was 56 ± 12 years, 54% were men, 38% received beta-blocker therapy and mean systolic and diastolic BP were 135 ± 24 and 78 ± 16 mmHg, respectively. Aortic root diameters were significantly larger in ADPKD patients than in controls (36.4 ± 4.1 versus 34.0 ± 3.7 mm, P < 0.0001). The Campens Z-scores (normalised on sex, age and body surface area) were significantly higher in ADPKD patients both for aortic root and ascending aorta ( Fig. 1 ). Moreover, aortic aneurisms, as defined by a Z score > 2 standard deviations, were present in 27 ADPKD patients (44%) versus 9 controls (15%, P < 0.001). There is an increased prevalence of aortic aneurysms in ADPKD patients, as compared with controls matched for common confounding factors for aortic dilation. Although systematic echocardiography is currently not recommended in ADPKD patients, our results strongly support echocardiographic screening for aorta aneurism and follow-up in this population.

Is serum copeptin a modifiable biomarker in autosomal dominant polycystic kidney disease?

The availability of disease-modifying drugs for the management of autosomal dominant polycystic kidney disease (ADPKD) has accelerated the need to accurately predict renal prognosis and/or treatment response in this condition. Arginine vasopressin (AVP) is a critical determinant of postnatal kidney cyst growth in ADPKD. Copeptin (the C-terminal glycoprotein of the precursor AVP peptide) is an accurate surrogate marker of AVP release that is stable and easily measured by immunoassay. Cohort studies show that serum copeptin is correlated with disease severity in ADPKD, and predicts future renal events [decline in renal function and increase in total kidney volume (TKV)]. However, serum copeptin is strongly correlated with creatinine, and its additional value as a prognostic biomarker over estimated glomerular filtration rate and TKV is not certain. It has also been suggested that copeptin could be a predictive biomarker to select ADPKD patients who are most likely to benefit from AVP-modifying therapies, but prospective data to validate this assumption are required. In this regard, long-term randomised clinical trials evaluating the effect of prescribed water intake on renal cyst growth may contribute to addressing this hypothesis. In conclusion, although serum copeptin is aligned with the basic pathogenesis of ADPKD, further rigorous studies are needed to define if it will contribute to enabling the delivery of personalised care in ADPKD.

Renal injury progression in autosomal dominant polycystic kidney disease: a look beyond the cysts.

Hypertension and progressive decline of renal function are among the common clinical manifestations in autosomal dominant polycystic kidney disease (ADPKD). At present, cyst formation in ADPKD patients is still considered the main pathogenic mechanism for the onset of these manifestations. However, the presence of polycystins in the vessels and the cilia of the endothelial cells and vascular smooth muscle cells, as well as development of hypertension prior to renal function decline and its prognostic role for the latter, indicate that polycystins may have an important role for endothelial damage in several vascular beds. Pathological polycystins induce intracellular calcium abnormalities, which affect various cellular organelles and functions and possibly lead not only to several abnormal biochemical reactions within endothelial cells, but also to an imbalance between oxidant and antioxidant capacity. Among the consequences of this process is accumulation of asymmetric-dimethylarginine, which not only participates in the induction and progression of renal damage, but also interferes with the normal vascular response due to nitric oxide (NO) inhibition. Reduced NO bioavailability would result in the long-run in relative vasoconstriction, impaired renal blood flow and vascular remodelling. This review summarizes the existing data from studies supporting that mechanisms other than cyst formation also contribute to the pathogenesis of hypertension and renal function decline in ADPKD.