Autosomal Dominant Polycystic Kidney Disease Patients Research Articles

SUN-199 URINARY ANGIOTENSINOGEN TO CREATININE RATIO (UAGT/CR) IS NOT A PREDICTIVE BIOMARKER FOR RENAL PROGRESSION IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE: KNOW-CKD STUDY

Decreased renal blood flow by cystic compression and subsequent hypertension has been suggested as one of the main mechanisms for renal progression in autosomal dominant polycystic kidney disease (ADPKD) and intrarenal renin-angiotensin-aldosterone system (RAAS) is known to play the major role in this process. Urinary angiotensinogen to creatinine ratio (UAGT/Cr) was suggested as a novel biomarker to reflect intrarenal RAAS activity. Previous study demonstrated that ADPKD patients have 5- to 6- fold higher level of UAGT/Cr compared to non-ADPKD CKD patients and the level of UAGT/Cr was associated with decreased renal function. However, whether UAGT/Cr can predict renal function decline or kidney growth has not been elucidated. This study was performed to evaluate UAGT/Cr in a prospective ADPKD cohort and demonstrate its usefulness as a predictive biomarker in ADPKD patients. From April 2011 to February 2016, a total of 364 ADPKD patients were enrolled in the prospective cohort called KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD). UAGT was measured by commercial sandwich enzyme-linked immunosorbent assay (ELISA) (Immuno-Biological Laboratories, Co., Ltd., Gunma, Japan) and adjusted by urinary creatinine (Cr) content. Serum Cr was measured by IDMS-traceable method at a central laboratory and glomerular filtration rate (GFR) was estimated by CKD-EPI(Cr) equation. Annual GFR decline rate was calculated from the difference between final and initial Cr divided by follow-up years. Total kidney volume (TKV) was measured upon enrollment and every two years afterwards. HtTKV was calculated by TKV divided by the height of the patient. The annual eGFR decline rate and HtTKV growth rate was compared among UAGT/Cr quartile groups. The variables that do not follow normal distribution was natural log-transformed before analysis. The mean age was 47 years and male were 184 (50.5%). Most of the patients were taking angiotensin converting enzyme inhibitors or angiotensin receptor blockers (85.9%). Baseline estimated GFR was 68.1±33.3 mL/min/1.73m2 and HtTKV was 740.7±541.6 cc/m. Mean UAGT.Cr was 16.3±45.3 μg/g. Ln(UAGT/Cr) was negatively correlated with estimated GFR (r2=0.03, p=0.001) and positively correlated with Ln(HtTKV) (r2=0.03, p=0.004). UAGT/Cr was significantly increased as CKD stage progressed (8.1±20.9 in stage 1 vs. 8.9±16.4 in stage 2 vs. 12.9±16.2 in stage 3 vs. 28.6±74.1 in stage 4 vs. 125.2±138.4 in stage 5, p<0.001). A total of 246 patients with relatively preserved GFR (>30 mL/min/1.73m2) were evaluated for the effect of UAGT/Cr upon prospective eGFR decline rate and HtTKV growth rate. The mean follow-up duration was 45.3±14.8 months. The highest quartile UAGT/Cr group showed higher systolic and diastolic blood pressure (131.9±13.6 and 83.0±10.9 mmHg, p<0.05), lower GFR at baseline (63.9±20.9 mL/min/1.73m2, p<0.001) and higher HtTKV (816.5±499.2 cc/m, p=0.079). However, neither annual GFR decline rate or HtTKV growth rate was statistically different among UAGT/Cr quartile groups. Ln(UAGT/Cr) was not associated with either annual GFR decline rate (r2=0.01, p=0.876) or Ln(HtTKV growth rate) (r2=0.036, p=0.761). UAGT/Cr is a marker of concurrent renal function and HtTKV. However, UAGT/Cr cannot predict renal progression in ADPKD.

Abstract 3459: PKD1 regulates susceptibility to ulcerative colitis and colorectal cancer

Abstract Compromised integrity of the epithelial barrier function of colon tissue associated with inflammatory bowel diseases (IBDs) or arising from tumor-elicited inflammation (TEI) are associated with and support formation of colorectal cancer (CRC). Apical tight junction (TJ) proteins, including multiple specific claudins, are critical in regulating TJ barrier function and paracellular permeability. Changes in TJ composition in the kidney are strongly linked to the etiology of autosomal dominant polycystic kidney disease (ADPKD), with ADPKD-inducing mutations in PKD1 causing non-leaky barriers that can withstand high hydrostatic pressure within renal cysts a hallmark of this common (1 in 500) inherited disease. Intriguingly, a large population study has found a decreased incidence of CRC in ADPKD patients. Based on these and other suggestive data, we hypothesized that loss of PKD1 would hinder development of ulcerative colitis and initiation of colitis associated cancer, based on reorganizing TJs and TEI in the colon. To evaluate the impact of Pkd1 loss on colon barrier function, we treated 10-12 week old wt or Pkd1fl/fl mice with tamoxifen-induced, Cre expression from the CreERT2 cassette for 5 days with 2.5% DSS in drinking water to induce acute colitis, compared to a no-DSS control group. For the wtcohort, treatment with DSS increased orally gavaged FITC-dextran detectable in serum versus controls. In contrast, no Pkd1-/- mice showed a similar DSS-dependent response to FITC-dextran, suggesting reinforced colon barrier function; further, histopathological assessment confirmed less DSS-induced damage in Pkd1fl/fl mice. Further, based on immunofluorescence (IF) analysis of tissue sections, claudins 4 and 7 associated with increased barrier function) strongly elevated in the colonic epithelium of Pkd1fl/fl versus wt mice, with the expressed proteins having consistently greater localization to cell junctions in Pkd1fl/fl versus wt mice. We also investigated the formation of CRC tumors, using a CDX2-ERT2/Cre model for tamoxifen-induced loss of Apc and/or Pkd1 in the colon to compare tumorigenesis in the Apcfl/fl, Apcfl/fl Pkd1fl/fl, and Apcfl/flPkd1fl/+ genotypes. We observed a highly significant progressive increase in the number and size of Apc mutation-induced tumors based on retention of the Pkd1 gene. Preliminary qRT-PCR analysis of these tumors shows that a Pkd1fl/fl genotype substantially increases CLDN4 in normal and tumor tissue, and decreases TNFα expression in tumors, suggesting reduced inflammation. This work and extended mechanistic characterization identifies PKD1 as a vital regulator of signaling systems already associated with colitis and CRC. Understanding the role of PKD1 and its effectors may provide useful information to genetic counselors assessing risk of IBD and CRC, and suggest therapeutic strategies. Citation Format: Anna S. Nikonova, Anna Kiseleva, Ilya Serebriiskii, Sergei Grivennikov, Erica A. Golemis. PKD1 regulates susceptibility to ulcerative colitis and colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3459.

MON-329 RAPID-ADPKD (RETROSPECTIVE EPIDEMIOLOGIC STUDY OF ASIAN-PACIFIC PATIENTS WITH RAPID DISEASE PROGRESSION OF AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE): DESIGN AND METHODS

Autosomal dominant polycystic kidney disease (ADPKD) patients reach end-stage renal disease (ESRD) in the 5th decade on average. For effective treatment and early intervention, identifying subgroups with rapid progression are important in ADPKD. However, there are no epidemiologic data regarding the clinical manifestations and disease progression of ADPKD patients from the Asia-pacific region. The RAPID-ADPKD is a multinational retrospective observational cohort study of ADPKD patients in the Asia-pacific area. This study was designed to identify the clinical characteristics of ADPKD patients with rapid progression, based on the change of renal function, kidney size and progression to ESRD. Seven hospitals from six regions (Australia, China, Hong Kong, South Korea, Taipei and Turkey) are participating in this study. ADPKD patients ≥18 years old, diagnosed by the unified ultrasound criteria and with estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73m2 at baseline will be included. The cohort will include patients with more than two records of eGFR, at least 24 months follow up data. Patients with severe heart failure, severe liver disease and/or other comorbidities that can effect renal function will be excluded. Demographic information, clinical characteristics, premorbid comorbidities, medications, eGFR, radiologic findings that can calculate height adjusted total kidney volume (htTKV), PKD-related complications and the PRO-PKD score will be collected using an electrical case report form. Rapid progression will defined as when any of following criteria are met: (i) an annual eGFR decline ≥5 mL/min/1.73m2 in 1 year and/or ≥2.5mL/min/1.73m2 per year over a period of 5 years; (ii) an increase in htTKV ≥ 5% per year from ≥3 radiologic images; (iii) Mayo classification 1C, 1D, or 1E or kidney length from ultrasonography of >16.5 cm’ (iv) PKD1 truncated mutation with early symptoms (PRO-PKD score >6). All other patients without any of the criteria are classified as slow progression. The clinical characteristics will be compared between patients with rapid progression and slow progression. In addition, the incidence rate, age of diagnosis, treatment complications between patients with rapid and slow progression will be analyzed. The clinical characteristic differences according to age groups will be analyzed as secondary analysis. The planned sample size of the cohort is 2,000 patients, and as October 8th 2018, data from 280 patients have been collected. RAPID-ADPKD is the first large-scale multinational retrospective observational study of ADPKD in Asia-Pacific region and will identify the clinical characteristics, risk factors for disease progression and patterns of complications in Asian populations with ADPKD.

SAT-259 DIFFERENT MARKERS OF ENDOTHELIAL DYSFUNCTION ARE ALTERED IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE PATIENTS WITH EARLY AND LATE DISEASE

Patients with autosomal dominant polycystic kidney disease (ADPKD) have a high incidence rate of hypertension and cardiovascular disease. Endothelial dysfunction (ED) has been reported in some patient ADPKD cohorts although published studies have been confounded by the inclusion of patients with significant chronic kidney disease (CKD), hypertension, anti-hypertensive drugs and other co-morbidities (age, smoking, high BMI). The major aim of this study was to test the hypothesis that ED was present in normotensive ADPKD patients with early disease (≥60ml/min/1.73m2) without confounding risk factors by assessing vascular function, serum and urine biomarkers in a single centre prospective study.

Multiple urinary tract infections are associated with genotype and phenotype in adult polycystic kidney disease.

Urinary tract infections (UTI) are one of the important clinical presentations in patients with autosomal dominant polycystic kidney disease (ADPKD). The association between UTI among genotypic and phonotypic properties of ADPKD patients is still obscure. Thus, we investigated the relationship between UTI and polycystin gene mutation with total kidney volume. Forty patients with ADPKD patients with a history of more than two UTI and age-gender-matched 40 ADPKD patients without UTI history enrolled in the study. Ambulatory blood pressure monitoring was performed in all participants. 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. ADPKD patients with UTI had lower eGFR values than those without UTI [64.9 (32.2-100.8) vs 89.5 (59.0-110.0) (p = 0.041)]. In addition, patients with UTI had significantly increased height-adjusted total kidney volume than patients without UTI [950 (290-1350) vs 345 (243-780.0) (p = 0.005)]. Multiple logistic regression analysis showed that the PKD1-truncating mutation and hTKV independently predicted UTI. The sensitivity and specificity of hTKV were 65% and 77% (cutoff > 727 cm3) with an area of under the ROC curve of 0.70 (95% CI 0.56-0.85, p = 005). ADPKD patients with larger kidneys and PKD1 mutation are susceptible to increased risk of multiple UTI. Additionally, renal function decreased in ADPKD patients with multiple UTI history.

Dysmetabolic markers predict outcomes in autosomal dominant polycystic kidney disease.

Overweight and obesity were recently associated with a poor prognosis in patients with autosomal dominant polycystic kidney disease (ADPKD). Whether the metabolic consequences of obesity as defined by the metabolic syndrome (MS) are also linked with disease progression remains untested. Eligible ADPKD patients with different stages of CKD (n = 105) and 105 non-diabetic controls matched for CKD stage were enrolled in the study. Groups were evaluated at baseline for presence of MS, blood markers of metabolism, homeostasis model assessment of insulin resistance (HOMA-IR) score, and biochemical markers of inflammation (hs-CRP, IL-1β, IL-6, TNF-α and PON-1). MS was defined according to the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III). Patients were followed for 12months and progression defined as a decrease in baseline eGFR > 10%. MS and hypertension were more prevalent amongst ADPKD patients than in the control group. Meanwhile, markers of inflammation such as hs-CRP (3.63 [3.45-5.17] vs. 4.2 [3.45-8.99] mg/dL; p = 0.014), IL-6 (21.65 [14.1-27.49] vs. 24.9 [16.23-39.4] pg/mL; p = 0.004) and IL-1β (21.33 [15.8-26.4] vs. 26.78 [18.22-35] pg/mL; p < 0.001) levels were all more elevated in ADPKD patients than in non-diabetic CKD subjects. In multivariate analysis having a truncating PKD1 mutation predicted (OR 1.25 [1.09-1.43]; p = 0.002) fulfilling the MS criteria. Finally, ADPKD patients fulfilling MS criteria had a significantly more rapid progression during 12months of follow-up than did those that did not (OR 3.28 [1.09-9.87]; p = 0.035). Our data supports the notion that dysmetabolisms part of the ADPKD phenotype and associated with a poor outcome, especially in patients with a truncating PKD1 mutation.

Association of Vitamin D Levels With Kidney Volume in Autosomal Dominant Polycystic Kidney Disease (ADPKD).

Vitamin D possesses renoprotective effects beyond mineral metabolism, potentially reducing arterial blood pressure and inflammation and vitamin D enzymes (CYP24A1 and CYP27B1) as well as vitamin D receptor (VDR) contribute to its homeostasis. In the present study, we aimed to determine vitamin D association with kidney volume, blood pressure parameters and inflammatory markers in ADPKD. This cross-sectional study, conducted from August 2011 through May 2016, evaluated 25(OH)D, 1,25(OH)2D and other hormonal/biochemical serum and urinary parameters, inflammatory markers and monocyte expression of VDR, CYP24A1, CYP27B1 in 74 ADPKD patients. The height-adjusted total kidney volume (htTKV) was determined by MRI and blood pressure (BP) measured through 24-h ambulatory BP monitoring (ABPM).Vitamin D insufficiency was present in 62% of patients and CYP24A1 was overexpressed in this group, raising a hypothesis of 25(OH)D increased catabolism. Serum 25(OH)D levels and VDR expression were negatively correlated with htTKV as was VDR with IL-6, IL-10, CRP, and NFκB. A multiple linear regression analysis with htTKV as dependent variable, including hypertension, CRP, eGFR, age, time since diagnosis, VDR, and 25(OH)D adjusted for season of the year showed that only the first three parameters were independent predictors of the former. There has been no association of serum 25(OH)D and VDR expression with ABPM parameters. Present findings suggested that low levels of serum 25(OH)D and VDR expression are associated with a higher kidney volume in ADPKD patients, but do not represent independent risk factors for htTKV.

Podocyte Injury in Autosomal Dominant Polycystic Kidney Disease

Background/Aims: Autosomal dominant polycystic kidney disease (ADPKD) is a tubulointerstitial disease. Different degrees of glomerular affection in ADPKD may affect the further course of disease in which it may hypothetically be secondary to the result of glomerular involvement causing podocyte injury. Our aim was to compare urinary excretion of podocin and podocalyxin, which are biomarkers of podocyte injury, and to assess their relationship with proteinuria and renal function in ADPKD. Methods: Fifty-six patients with ADPKD and 28 volunteers were enrolled to study. Podocin, podocalyxin protein levels, and proteinuria were measured in urine. Patients were categorized based on their estimated glomerular filtration rate (eGFR). Results: Patients with ADPKD had higher podocin and podocalyxin levels compared to the control group. The levels of podocin and podocalyxin were higher in ADPKD patients both with eGFR ≥60 mL/min/1.73 m² and with eGFR <60 mL/min/1.73 m² than in controls. The levels of podocin and podocalyxin were higher in ADPKD patients with eGFR <60 mL/min/1.73 m² than in ADPKD patients with eGFR ≥60 mL/min/1.73 m². Podocin and podocalyxin were negatively correlated with eGFR and positively correlated with urine protein to creatinine ratio in ADPKD patients. Conclusion: Urine biomarkers of podocytes injury were significantly higher in ADPKD patients even in the early stage of the disease than in the control group. It should be clarified whether these biomarkers can provide new prognostic parameters for disease surveillance.

Comparison of fasting versus non-fasting lipid profile in school children aged 9-11

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most prevalent causes of kidney transplantation (KTx) worldwide. About 40% of ADPKD patients require peritransplant native kidney nephrectomy (NKN). The decision regarding qualification for NKN usually relies on the surgeon’s expertise. Currently used qualification criteria are subjective and incomparable between clinical centers. There is a need to identify the indications for NKN by applying radiologically based methods to the decision-making process.To assess the usefulness of radiologic parameters in the qualification process of ADPKD waitlist candidates for the NKN procedure.A retrospective, observational study in a cohort of ADPKD patients in a single institution was conducted. The study included the participation of waitlist candidates and kidney transplant recipients with computed tomography (CT) or magnetic resonance imaging (MRI) obtained in the peritransplant period. The correlation of imaging-based measurements with the results of clinical qualification for the NKN procedure was assessed.In the years 2012 to 2019, 19 patients completed the inclusion criteria. Total kidney volume (TKV) values were statistically more significant in the NKN group (n = 10) than in the non-NKN group (n = 9), with medians of 3351 mL and 1654 mL, respectively (P = .016). There were no significant differences between the groups in terms of the ratio of complex cyst volume to TKV, with the NKN group having a ratio of 19.2% and the non-NKN group 15.6% (P = .095). Venous compression was found only in the NKN group (n = 2).TKV highly correlates with the results of clinical qualification for NKN. Radiologic assessment enables the detection of complicated cysts or clinically silent states of venous compression. Pretransplant imaging should be routinely obtained.

Identifying gene mutations of Chinese patients with polycystic kidney disease through targeted next-generation sequencing technology.

BackgroundPolycystic kidney disease (PKD) is the most common hereditary kidney disease. The main mutational genes causing autosomal dominant polycystic kidney disease (ADPKD) are PKD1 and PKD2 as well as some rare pathogenic genes. Unilateral PKD is rare in clinics, and its association with gene mutations is unclear.MethodsTargeted next‐generation sequencing (NGS) was performed to detect the renal ciliopathy‐associated genes (targeted NGS panel including 63 genes) in PKD patients.ResultsForty‐eight PKD1 and PKD2 mutation sites were detected in 44 bilateral PKD patients, of which 48 were PKD1 mutation sites (87.5%) and six were PKD2 mutation sites (12.5%). All of which exhibited typical ADPKD. Furthermore, we detected HNF1B heterozygous mutations in three families. Although these three patients showed HNF1B heterozygous mutations, their clinical characteristics differed and showed phenotypic heterogeneity.ConclusionsTargeted NGS panel was helpful in detecting typical ADPKD patients and even in non‐typical PKD patients. Macromutation in HNF1B may lead to bilateral PKD. The 16 novel PKD gene mutation sites and two novel PKD2 gene mutation sites discovered in this study have some significance in genetic counseling for ADPKD patients, and increase the number of studied families and expand the mutation database of ADPKD.

Pancreatic Cysts and Intraductal Papillary Mucinous Neoplasm in Autosomal Dominant Polycystic Kidney Disease.

Pancreatic lesions in autosomal dominant polycystic kidney disease (ADPKD) are primarily cysts. They are increasingly recognized, with isolated reports of intraductal papillary mucinous neoplasia (IPMN). Retrospective study to determine prevalence, number, size, and location of pancreatic abnormalities using abdominal magnetic resonance imaging (MRI) of genotyped ADPKD patients (seen February 1998 to October 2013) and compared with age- and sex-matched non-ADPKD controls. We evaluated presentation, investigation, and management of all IPMNs among individuals with ADPKD (January 1997 to December 2016). Abdominal MRIs were examined for 271 genotyped ADPKD patients. A pancreatic cyst lesion (PCL) was detected in 52 patients (19%; 95% confidence interval, 15%-23%). Thirty-seven (71%) had a solitary PCL; 15 (28%) had multiple. Pancreatic cyst lesion prevalence did not differ by genotype. Intraductal papillary mucinous neoplasia was detected in 1% of ADPKD cases. Among 12 IPMN patients (7 branch duct; 5 main duct or mixed type) monitored for about 140 months, 2 with main duct IPMNs required Whipple resection, and 1 patient died of complications from small-bowel obstruction after declining surgical intervention. With MRI, PCLs were detected in 19% and IPMNs in 1% of 271 ADPKD patients with proven mutations, without difference across genotypes. Pancreatic cyst lesions were asymptomatic and remained stable in size.

Outcomes of patients with autosomal-dominant polycystic kidney disease on peritoneal dialysis: A meta-analysis.

Complications related to peritoneal dialysis (PD) in patients with autosomal-dominant polycystic kidney disease (ADPKD), including intraperitoneal rupture of renal cyst, hernia, membrane failure and peritonitis, have been reported. However, long-term clinical outcomes of ADPKD patients on PD remain unclear. We performed this meta-analysis to assess the risks of death, technique failure and peritonitis in ADPKD patients on PD. A systematic review was conducted using MEDLINE, EMBASE and Cochrane databases from inception to October 2017 to identify studies that evaluated the outcomes of ADPKD patients on PD, including the risks of death, technique failure and peritonitis. Non-ADPKD patients on PD were used as controls. Effect estimates from the individual study were extracted and combined using the random-effect, generic inverse variance method of DerSimonian and Laird. Twelve cohort studies with a total of 14 673 patients on PD (931 ADPKD and 13 742 non-ADPKD patients) were enrolled. Compared with non-ADPKD status, ADPKD was associated with significantly decreased mortality risk with pooled odds ratio (OR) of 0.68 (95% confidence interval (CI), 0.53-0.86; I2 = 0). There were no associations of ADPKD with the risks of technique failure of PD and peritonitis with pooled OR of 0.93 (95% CI, 0.79-1.10; I2 = 0) and 0.88 (95% CI, 0.75-1.05; I2 = 0), respectively. We found no publication bias as assessed by Egger's regression asymmetry test, with P = 0.90, 0.28 and 0.60 for the risks of mortality, technique failure and peritonitis in ADPKD patients on PD, respectively. Compared with non-ADPKD patients on PD, our study demonstrates that ADPKD patients on PD have 0.68-fold decreased mortality risk. There are no associations of ADPKD status with the risks of technique failure or peritonitis.

Modelling the long-term benefits of tolvaptan therapy on renal function decline in autosomal dominant polycystic kidney disease: an exploratory analysis using the ADPKD outcomes model

BackgroundThe short-term efficacy of tolvaptan in patients with autosomal dominant polycystic kidney disease (ADPKD) has been demonstrated across several phase 3 trials, while the ADPKD Outcomes Model (ADPKD-OM) represents a validated approach to predict natural disease progression over a lifetime horizon. This study describes the implementation of a tolvaptan treatment effect within the ADPKD-OM and explores the potential long-term benefits of tolvaptan therapy in ADPKD.MethodsThe effect of tolvaptan on ADPKD progression was modelled by applying a constant treatment effect to the rate of renal function decline, consistent with that observed in the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes trial (TEMPO 3:4; ClinicalTrials.gov identifier NCT00428948). Predictions generated by the ADPKD-OM were compared against aggregated data from a subsequent extension trial (TEMPO 4:4; ClinicalTrials.gov identifier NCT01214421) and the Replicating Evidence of Preserved Renal Function an Investigation of Tolvaptan Safety Efficacy in ADPKD trial (REPRISE; ClinicalTrials.gov identifier NCT02160145). Following validation, an application of the ADPKD-OM sought to estimate the benefit of tolvaptan therapy on time to end-stage renal disease (ESRD), in a range of ADPKD populations.ResultsModel validation against TEMPO 4:4 and REPRISE demonstrated the accuracy and generalisability of the tolvaptan treatment effect applied within the ADPKD-OM. In simulated patients matched to the overall TEMPO 3:4 trial population at baseline, tolvaptan therapy was predicted to delay the mean age of ESRD onset by five years, compared to natural disease progression (57 years versus 52 years, respectively). In subgroup and sensitivity analyses, the estimated delay to ESRD was greatest among patients with CKD stage 1 at baseline (6.6 years), compared to CKD 2 and 3 subgroups (4.7 and 2.7 years, respectively); and ADPKD patients in Mayo subclasses 1C–1E.ConclusionsThis study demonstrated the potential for tolvaptan therapy to delay time to ESRD, particularly among patients with early-stage CKD and evidence of rapidly progressing disease. Data arising from this study highlight the value to be gained by early intervention and long-term treatment with tolvaptan, which may alleviate the economic and societal costs of providing care to patients who progress to ESRD.

Correlation of serum galectin-3 level with renal volume and function in adult polycystic kidney disease.

The decrease in kidney functions in autosomal dominant polycystic kidney disease (ADPKD) is strongly correlated with the severity and growth of kidney cysts. Total kidney volume (TKV) was shown to be an early marker of the severity of the disease and a predictor of reduction in kidney functions. New treatment approaches for ADPKD have led to a need for easily applicable strong biomarkers predicting progression of the disease. The profibrotic mediator of galectin-3 (Gal-3) is linked to development of renal fibrosis. The study included 74 patients with ADPKD diagnosis and 40 healthy controls. The TKV of patients was calculated using the manual tracing method on MR images. The serum Gal-3 levels of patient and healthy control groups were measured with the ELISA method. The correlations between serum Gal-3 value with TKV and kidney function were assessed in patients. As the stage of chronic kidney disease (CKD) increased, serum Gal-3 and TKV values increased (p < 0.001, p = 0.049, respectively). Correlation analysis found a negative relationship between serum Gal-3 levels and eGFR (r: -0.515, p < 0.001); however, there was no relationship between serum Gal-3 and TKV (r = 0.112, p = 0.344). Linear regression analysis showed the major parameter affecting Gal-3 was eGFR (p = 0.016). In our study, we showed that renal impairment is an important determinant of Gal-3, and there is no correlation of Gal-3 and TKV in ADPKD. As a result, there is an urgent clinical need for new biomarkers to identify individuals with the chance of treatment in the early stage among ADPKD patients.

Identification of novel mutations and risk assessment of Han Chinese patients with autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease in humans and is caused by mutations in the PKD1 or PKD2 gene. ADPKD is heterogeneous with regard to locus and allele heterogeneity and phenotypic variability. Using targeted capture associated with next generation sequencing (NGS), we performed a mutational analysis of Han Chinese patients with ADPKD from 62 unrelated families. Multivariate Cox proportional hazard modelling of their different clinical characteristics and mutation classes was performed. The detection rate for a PKD1 and PKD2 mutation in the Chinese ADPKD patients was 95.2% (59/62). We identified pathogenic mutations in 64.4% (38/59) of patients, including 32PKD1 mutations (15 nonsense mutations, 15 frameshift mutation, one splice mutation, and one large deletion) and six PKD2 mutations (three nonsense mutations and three frameshift mutations). Of the pathogenic variants we identified, 50% (19/38) were novel variants and 50% (19/38) were known variants. Patients with PKD2 mutations had milder and indistinguishable phenotypes. Significant phenotypic differences were observed among the various types of PKD1 mutations. Our results show that targeted capture associated with next-generation sequencing is an effective strategy for genetically testing ADPKD patients. This mutation analysis of ADPKD in Han Chinese extends our understanding of the genetic diversity of different ethnic groups, enriches the mutation database, and contributes to the genetic counselling of ADPKD patients.

Mutation analyses by next-generation sequencing and multiplex ligation-dependent probe amplification in Japanese autosomal dominant polycystic kidney disease patients.

Autosomal dominant polycystic kidney disease (ADPKD), one of the most common hereditary kidney diseases, causes gradual growth of cysts in the kidneys, leading to renal failure. Owing to the advanced technology of next-generation sequencing (NGS), genetic analyses of the causative genes PKD1 and PKD2 have been improved. We performed genetic analyses of 111 Japanese ADPKD patients using hybridization-based NGS and long-range (LR)-PCR-based NGS. Additionally, genetic analyses in exon 1 of PKD1 using Sanger sequencing because of an extremely low coverage of NGS and those using multiplex ligation-dependent probe amplification (MLPA) were performed. The detection rate using NGS for 111 patients was 86.5%. One mutation in exon 1 of PKD1 and five deletions detected by MLPA were identified. When combined, the total detection rate was 91.9%. Although NGS is useful, we propose the addition of Sanger sequencing for exon 1 of PKD1 and MLPA as indispensable for identifying mutations not detected by NGS.

Erken Evre Otozomal Dominant Polikistik Böbrek Hastalığında; FGF-23 İnfamasyon ve Demir Metabolizması

To investigate the correlation of Fibroblast Growth Faktör-23 (sFGF-23) with iron status, inflammation and carotid intima-media thickness (CIMT) in the early stages of autosomal dominant polycystic kidney disease (ADPKD). Forty ADPKD patients (24 female) with normal creatinine levels and 40 healthy volunteers (21 female) were included in the study. Serum FGF-23 levels were measured using the ELISA technique. The associations between sFGF-23 with CIMT, hs-CRP, neutrophil lymphocyte ratio (NLR) and iron parameters were evaluated using correlation analysis. Patients’ sFGF-23 levels were significantly higher [245 (182-963) pg/mL; vs. 219.6 (34-494) pg/mL], (P< 0.001). NLR and hs-CRP were also found to be statistically higher in patients than controls (P< 0.001 and P= 0.003, respectively). CIMT was significantly higher in the patient group (P= 0.037). There were statistically significant negative correlations between sFGF-23 and calcium, hemoglobin, hematocrit, serum iron, ferritin, and NLR (P= 0.009, P= 0.035, P= 0.002, P= 0.033, P= 0.017, P= 0.023, respectively), and positive correlations with phosporus, total iron binding capacity and sFGF-23 (P= 0.010, P= 0.049, respectively). There was no statistically significant correlation between sFGF-23 and PTH, hs-CRP and CIMT. In multivariate lineer regression analysis, serum phosphorus level was statistically significiant independent risk factor for the determinantion of sFGF-23 level [B: 0.318, OR:130,662(32,715-228,610), P=0.010]. Our study results support an inverse relationship between sFGF-23 and iron deficiency but no relationship between sFGF-23 and inflammation and atherosclerosis in the early stages of ADPKD.

Uroflowmetry alterations in patients with autosomal dominant polycystic kidney disease.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a heterogeneous inherited disease characterized by renal and extrarenal manifestations with progressive fluid-filled cyst development leading to end-stage renal disease. Our aim was to evaluate the prevalence of obstructive urological disease in ADPKD patients and possible associations with endothelial dysfunction, nutritional, metabolic and inflammatory markers. The study included ADPKD patients and control group, who carried out uroflowmetry, an assessment of renal function, metabolic and nutritional parameters and an evaluation of endothelial dysfunction and atherosclerotic markers, such as Renal Resistive Index (RRI), Intima-Media Thickness (IMT) and Flow-Mediated Dilation (FMD). We enrolled 37 ADPKD patients (20 males with 51.0 ± 14.3 years) and 34 control group (18 males with 60.7 ± 14.4 years). We showed a significant reduction in Max Flow Rate (Qmax) (p ≤ 0.001), age (p = 0.006), FMD (p = 0.023) and Voiding Volume (p = 0.053), in addition to a significant increase in Voiding Time and Diastolic Blood Pressure (p ≤ 0.001, p = 0.049; respectively) in ADPKD patients with respect to control group. Moreover, we found a negative correlation between Qmax and creatinine (r= -0.44, p = 0.007), RRI (r= -0.49, p ≤0.001) and intact Parathyroid Hormone (r = -0.329, p = 0.046), while we found a positive correlation between Qmax and MDRD (r = 0.327, p = 0.048) and between Voiding Time and serum uric acid (r= 0.34, p = 0.039) in ADPKD patients with respect to control group. In our study, we showed an elevated prevalence of urological functional diseases in ADPKD patients; therefore, we suggest to include uroflowmetry in the assessment of these patients, considering the non-invasiveness, repeatability and low cost of the exam. An early intervention could slow down the progression of renal damage and an early screening of the main cardiovascular risk factors could reduce the high morbidity and mortality in ADPKD patients.

Baseline characteristics of the autosomal-dominant polycystic kidney disease sub-cohort of the KoreaN cohort study for outcomes in patients with chronic kidney disease.

The aim of this study was to describe the baseline characteristics of autosomal-dominant polycystic kidney disease (ADPKD) in a cohort of Korean patients with chronic kidney disease (CKD). From April 2011 to February 2016, patients with CKD stage 1-5 (pre-dialysis) were enrolled as an ADPKD sub-cohort of the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease. Baseline characteristics, the correlation of kidney and liver volume and kidney function and the factors associated with kidney function were analysed. A total of 364 ADPKD patients with a mean estimated glomerular filtration rate (eGFR) of 68.1 ± 33.3 mL/min per 1.73 m2 (50.5% male with a mean age of 47.0 ± 10.6 years) were enrolled from nine hospitals in Korea. Initially, 55.8% of the patients were asymptomatic, and pain was the most common symptom (12.9%); 87.6 and 77.5% of the patients had hypertension and hepatic cysts, respectively. The height-adjusted total kidney volumes (htTKV) were higher in male patients than in female patients. In contrast, the height-adjusted total liver volumes were higher in female patients than in male patients. The decrease rate of eGFR depending on Log(htTKV) was larger in the group aged between 41 and 50 years than the other age groups. Older age, a higher 24-h urine protein excretion, larger htTKV and hyperuricemia were independently associated with lower eGFR, whereas using febuxostat was independently associated with higher eGFR. This sub-cohort will provide clinical characteristics and outcomes of Korean ADPKD patients, which can be compared with those of other previous cohorts. We have identified factors associated with advanced-stage CKD in Korean patients with ADPKD.

Pretransplant Nephrectomy for Large Polycystic Kidneys in ADPKD (Autosomal Dominant Polycystic Kidney Disease) Patients: Is Peritoneal Dialysis Recovery Possible after Surgery?

The choice of modality for renal replacement therapy in patients with ADPKD varies, often based on patient choice, physician-related factors, and resource availability. For a long time peritoneal dialysis (PD) was considered as relative contraindication due to the possible limited intraperitoneal space. In recent years, some studies suggested it is a valid option also in patients with ADPKD to be considered as a first line treatment in potentially fit patients. Diuresis volume lowering and potential permanent damage of peritoneal integrity, both leading to a necessary switch to haemodialysis, are the two most important dangers after nephrectomy, especially if bilateral, in PD patients. We performed a retrospective analysis of patient underwent native polycystic kidney nephrectomy in order to state the possibility to recover peritoneal dialysis after surgery.