Polycystic Kidney Disease Patients Research Articles

Targeting and therapeutic peptide-based strategies for polycystic kidney disease.

Polycystic kidney disease (PKD) is characterized by progressive cyst growth and is a leading cause of renal failure worldwide. Currently, there are limited therapeutic options available to PKD patients, and only one drug, tolvaptan, has been FDA-approved to slow cyst progression. Similar to other small molecule drugs, however, tolvaptan is costly, only moderately effective, and causes adverse events leading to high patient dropout rates. Peptides may mitigate many drawbacks of small molecule drugs, as they can be highly tissue-specific, biocompatible, and economically scaled-up. Peptides can function as targeting ligands that direct therapies to diseased renal tissue, or be potent as therapeutic agents themselves. This review discusses various aberrant signaling pathways in PKD and renal receptors that can be potential targets of peptide-mediated strategies. Additionally, peptides utilized in other kidney applications, but may prove useful in the context of PKD, are highlighted. Insights into novel peptide-based solutions that have potential to improve clinical management of PKD are provided.

The relationship between liver cyst volume and QOL in Japanese ADPKD patients.

Although it is widely accepted that the autosomal dominant polycystic kidney disease (ADPKD) patients with large liver cysts have a significant decrement in quality of life (QOL), there is insufficient evidence that clearly demonstrates the relationship between the size of the liver cysts and QOL. Therefore, we started this prospective longitudinal study to investigate the impact of liver cysts on QOL. We grouped the 111 included ADPKD patients into 4 groups (control group A; < 25%, group B; 25-49%, group C; 50-75%, group D; > 75%) according to liver cysts-parenchyma ratio (CPR). QOL was measured by FANLTC + FACT-Hep scores. We compared QOL scores and several clinical parameters amongst these groups for 3years. The number of patients in group A, B, C, and D was 31, 14, 14, and 23, respectively. Although there were no significant differences in AST (p = 0.107), ALT (p = 0.925), and serum albumin (p = 0.212) between the four groups, platelet count was significantly decreased along with the extension of cyst volume (p = 0.030). Overall, the mean FANLTC and FACT-Hep scores were 71.8 ± 12.5, and 32.4 ± 5.8, respectively. FANLTC (p = 0.017) and FACT-Hep scores (p = 0.003) were significantly decreased with increasing cyst volume. From the data collected at the time of registration, multivariate linear regression analysis demonstrated that the CPR had a significant influence on FANLTC and FACT-Hep scores. In this cross-sectional and prospective longitudinal study, we demonstrate the relationship between liver cyst volume and QOL in ADPKD patients. We hope to establish the long-term influence on QOL in this ongoing prospective longitudinal study.

Evaluation of common polymorphisms of eNOS gene and ACE gene in autosomal dominant polycystic kidney disease patients and their association with hypertension and renal failure

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is the most hereditary renal disease that leads to end-stage renal disease (ESRD). Objectives: Since there is no available parameter to assess the clinical course of ADPKD and its outcome, yet, the aim of our study was evaluation of the association of common polymorphisms of eNOS and ACE genes with clinical manifestations (kidney failure and hypertension) in ADPKD. Patients and Methods: Seventy-five ADPKD patients and 100 control subjects participated in our study. Around 7.5 cc of whole blood was taken from each participant and sent to the genetic laboratory. DNA was obtained from them by the phenol chloroform extraction and ethanol precipitation techniques. Then genotyping for I/D polymorphism of ACE gene and Glu298 ASP and T786C polymorphisms of eNOS gene was performed by PCR electrophoresis and molecular evaluation by special primers for two genes. Results: The frequency of DD polymorphism of ACE gene and TC polymorphism of T786C of eNOS were considerably elevated in ADPKD individuals than control subjects. No significant difference between groups regarding Glu298 ASP polymorphisms of eNOS gene was detected. In ADPKD patients, 29 patients (39%) had hypertension, 5 patients (6.7%) had diabetes and 43 patients (57%) had glomerular filtration rate (GFR) below 60 mL/min/1.73 m2 . The polymorphisms of ACE and eNOS genes were not meaningfully different regarding diabetes, high blood pressure, GFR and plasma creatinine in ADPKD individuals (P&gt;0.05). Conclusion: In our study, we could not find any association between polymorphisms of ACE and eNOS genes with renal insufficiency and hypertension in ADPKD patients.

Idiosyncratic hepatic toxicity in autosomal dominant polycystic kidney disease (ADPKD) patient in combined treatment with tolvaptan and amoxicillin/clavulanic acid: a case report

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is a hereditary disease characterized by the presence of renal cysts. Over time the expanding cysts lead to progressive renal failure. The use of tolvaptan, a V2-receptor antagonist, was recently approved in ADPKD patients. It was demonstrated that tolvaptan get slower decline in Kidney function compared with placebo. Idiosyncratic hepatic toxicity was described in patients receiving tolvaptan, with elevations in aminotransferases levels. We describe the first case reported in the literature in which hepatic toxicity is caused by the association of amoxicillin/clavulanic acid and tolvaptan.Case presentationA 41 years old woman with diagnosis of ADPKD had been in treatment with tolvaptan for 16 weeks when an elevation of liver enzyme levels was detected. She had taken autonomously amoxicillin/clavulanic acid (in doses of 825/175 mg twice a day for 7 days) about 5 weeks before.The timing of the event and the kind of hepatocellular injury could be attributed to the concomitance of medication of tolvaptan and amoxicillin/clavulanic acid.ConclusionWe highlight the need to careful monitor hepatic enzyme levels in order to recognize early hepatic side effects in ADPKD patients in treatment with tolvaptan and amoxicillin/clavulanic acid.

Nocturnal Hemodialysis Compared with Conventional Dialysis for End-Stage Renal Disease Treatment in Polycystic Kidney Disease Patients

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cause of end-stage renal disease (ESRD). Little is known about outcomes after in-center nocturnal hemodialysis (NHD) treatment in ADPKD patients with ESRD. Objectives: This study aimed to evaluate the effects of in-center NHD compared with conventional hemodialysis (CHD) and peritoneal dialysis (PD) in ADPKD. Methods: We used data of ADPKD adult patients with ESRD in the hospital database from 2000 to 2016. Propensity score matching, competing-risk regression, and Cox regression models were used for analysis. Results: A total of 170 ADPKD patients were included. The median follow-up time was 5.5 years. In the overall multivariate-adjusted analysis, no significant difference of mortality risk was found in NHD vs. CHD (hazard ratio [HR] 1.33, 95% CI 0.26–6.73, p = 0.31) and PD (HR 1.06, 95% CI 0.14–7.71, p = 0.55), respectively. The overall survival rate also was not significantly different among the 3 groups (p = 0.88). Based on the propensity score, 26 patients on CHD and 26 patients on PD were successfully matched to 13 NHD patients. In the matched analysis, NHD was not associated with a lower risk of mortality compared with CHD (HR 2.14, 95% CI 0.33–14.00, p = 0.31) and PD (HR 0.68, 95% CI 0.52–8.94, p = 0.55). The result was similar when treating renal transplantation as a competing event. However, NHD was associated with a lower rate of complications (38.5 vs. 84.6%, p = 0.003) and a higher level of serum albumin (p < 0.001) compared with PD. Conclusions: NHD may not be a better choice in survival compared with conventional dialysis modalities for ADPKD patients in this pilot study. Patients in NHD have fewer complications than PD. Future studies with large sample sizes and longer follow-up are required.

Evolution of metabolic syndrome components in patients with autosomal-dominant polycystic kidney disease: a six-year follow-up study

Aim: Long-term studies show that some metabolic syndrome (MS) components deteriorate renal function in autosomal dominant polycystic kidney disease (ADPKD) patients. The aim of this 6-year follow-up was to analyze early changes of all MS components and their associations with kidney function in the nondiabetic ADPKD patients with normal renal function, compared to controls. Material/Methods: The follow-up physical and laboratory examinations were performed for 39 ADPKD patients (age 43.7 ± 11.4 years) and 44 controls (43.5 ± 9.1 years). Results: We noticed a significant increase in weight, body mass index (BMI), waist, total and LDL cholesterol, C-peptide, uric acid, creatinine and significant decline of HbA1c and e-GFR in the ADPKD group. Increases in waist, uric acid and creatinine concentrations were significantly higher in the ADPKD patients than controls. Both groups showed similar rates of prediabetes, while diabetes developed in 5 controls (with 4 cases of type 2 diabetes and one case of type 1), but not in the ADPKD group (11% vs 0%, P = 0.06 for diabetes, 9% vs 0%, P = 0.12 for type 2 diabetes). The ADPKD group showed a significantly higher percentage of obesity, waist circumferences, systolic/diastolic blood pressure, concentrations of creatinine, urea and uric acid and lower e-GFR. The MS prevalence was comparable; however, the number of MS components was significantly higher in the ADPKD patients (median 2 vs. 1, p = 0.001). Conclusions: The presence of MS does not influence the rate of renal failure progression in nondiabetic ADPKD patients with normal renal function at a 6-year follow-up.

Two cases of fungal cyst infection in ADPKD: is this really a rare complication?

BackgroundCyst infection is a prevalent complication in autosomal dominant polycystic kidney disease (ADPKD) patients, however therapeutic and diagnostic approaches towards this condition remain unclear. The confirmation of a likely episode of cyst infection by isolating the pathogenic microorganism in a clinical scenario is possible only in the minority of cases. The available antimicrobial treatment guidelines, therefore, might not be appropriate to some patients.Case presentationWe describe two unique cases of kidney cyst infection by Candida albicans, a condition that has not been previously described in literature. Both cases presented clear risk factors for Candida spp. infection. However, since there was no initial indication of cyst aspiration and culture, antifungal therapy was not immediately started and empirical treatment was initiated as recommended by the current guidelines. Antifungal treatment was instituted in both cases along the clinical course, according to their specificities.ConclusionOur report highlights the possibility of Candida spp. cyst infection. Failure of clinical improvement with antibiotics should raise the suspicion of a fungal infection. Identification of infected cysts should be pursued in such cases, particularly with PET-CT, and when technically possible followed by cyst aspiration and culture to guide treatment. Risk factors for this condition, such as Candida spp. colonization, previous antimicrobial therapy, hemodialysis, necrotizing pancreatitis, gastrointestinal/hepatobiliary surgical procedure, central venous catheter, total parenteral nutrition, diabetes mellitus and immunodeficiency (neutropenia < 500 neutrophils/mL, hematologic malignancy, chemotherapy, immunosuppressant drugs), should be also considered accepted criteria for empirical antifungal therapy.

Left ventricular hypertrophy in a contemporary cohort of autosomal dominant polycystic kidney disease patients

BackgroundPatients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) often develop hypertension in childhood or early adulthood. Although this could result in left ventricular hypertrophy (LVH), a major risk factor for cardiovascular morbidity and mortality, prior studies of LVH in ADPKD have yielded conflicting results. We estimated the prevalence of LVH using consensus echocardiography criteria and examined the independent association of ADPKD severity with LV mass in a contemporary cohort of ADPKD patients.MethodsAdults with ADPKD and eGFR> 15 ml/min/1.73m2 were enrolled in a single-center study. Left Ventricular Mass (LVM) was quantified using 2D echocardiography, and LVH was defined using gender-specific cut-points of LVM and LVM indexed to body surface area (LVMI) from consensus guidelines. Total Kidney Volume (TKV) was quantified using Magnetic Resonance Imaging, and GFR was estimated from serum creatinine using the CKD-Epi equation. Multiple linear regression was used to estimate the association of TKV and eGFR with LVM and LVMI, adjusting for potential confounders.ResultsAmong 126 participants (78% with hypertension), median age was 46 years, median eGFR 63 ml/min/1.73 m2, and median [IQR] systolic blood pressure was 125 [116–133] mmHg. Prevalence of LVH was 21.4% as defined by LVMI and was not significantly different (p = 0.8) between those with and without HTN, and was similar (21.4%) after excluding those (N = 21) with known cardiac disease. Greater TKV and lower eGFR were directly correlated with greater LVMI (p = .016 and p < .001, respectively). In multiple linear regression models accounting for potential confounders including blood pressure, greater TKV was positively associated with LVM ( hat{beta} =0.19, p = 0.04).ConclusionsIn a contemporary cohort of ADPKD patients with well-controlled blood pressure, the prevalence of LVH is high, and ADPKD severity as reflected by TKV is independently associated with greater LV mass. These results may suggest a relationship between ADPKD pathophysiology and increased LV mass.

Native Nephrectomy before and after Renal Transplantation in Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD).

The aim of this study was 1) to evaluate and compare pre-, peri-, and post-operative data of Autosomal Dominant Polycystic Kidney Disease (ADPKD) patients undergoing native nephrectomy (NN) either before or after renal transplantation and 2) to identify advantages of optimal surgical timing, postoperative outcomes, and economical aspects in a tertiary transplant centre. This retrospective analysis included 121 patients divided into two groups—group 1: patients who underwent NN prior to receiving a kidney transplant (n = 89) and group 2: patients who underwent NN post-transplant (n = 32). Data analysis was performed according to demographic patient details, surgical indication, laboratory parameters, perioperative complications, underlying pathology, and associated mortality. There was no significant difference in patient demographics between the groups, however right-sided nephrectomy was performed predominantly within group 1. The main indication in both groups undergoing a nephrectomy was pain. Patients among group 2 had no postoperative kidney failure and a significantly shorter hospital stay. Higher rates of more severe complications were observed in group 1, even though this was not statistically significant. Even though the differences between both groups were substantial, the time of NN prior or post-transplant does not seem to affect short-term and long-term transplantation outcomes. Retroperitoneal NN remains a low risk treatment option in patients with symptomatic ADPKD and can be performed either pre- or post-kidney transplantation depending on patients’ symptom severity.

Cardiac function assessed by myocardial deformation in adult polycystic kidney disease patients

BackgroundPatients with autosomal dominant polycystic kidney disease (ADPKD) have an increased risk of cardiovascular morbidity and mortality. Impaired left ventricular (LV) global longitudinal strain (GLS) can be a sign of subclinical cardiac dysfunction even in patients with otherwise preserved ejection fraction (EF). Transmitral early filling velocity to early diastolic strain rate (E/SRe) is a novel measure of LV filling pressure, which is often affected early in cardiac disease.MethodsA total of 110 ADPKD patients not on dialysis were included in this prospective study. All patients underwent an extensive echocardiographic examination including two-dimensional speckle tracking. GLS and strain rates were measured. The distribution of GLS and E/SRe was determined and patient characteristics were compared by median levels of GLS (− 17.8%) and E/SRe (91.4 cm). Twenty healthy participants were included as control group.ResultsThere was a significantly worse GLS in the ADPKD patients (mean: − 17.8 ± 2.5%) compared to the healthy controls (mean: − 21.9 ± 1.9%), p < 0.001. The same was true for E/SRe (mean: 10.0 ± 0.3 cm) compared to the control group (mean: 6.5 ± 0.3 cm), p < 0.001. In simple logistic regression, male gender (OR: 4.74 [2.10–10.71], p < 0.001), fasting glucose (odds ratio (OR) 1.05 [1.01–1.10], p = 0.024), htTKV (OR: 1.07 [1.01–1.13], p = 0.013), HDL cholesterol (OR: 0.97 [0.94, 0.996], p = 0.025), triglycerides (OR: 1.01 [1.00–1.02], p = 0.039), hemoglobin (OR: 1.50 [1.11–2.04], p = 0.009), and β-blocker use (OR: 1.07 [1.01, 1.13], p = 0.013) were all associated with higher GLS. After multivariate logistic regression with backward model selection, only male gender (OR: 5.78 [2.27–14.71], p < 0.001) and β-blocker use (OR: 14.00 [1.60, 122.51], p = 0.017) remained significant. In simple logistic regression models, BMI (OR: 1.11 [1.02–1.20], p = 0.015), systolic blood pressure (OR: 1.03 [1.00–1.06], p = 0.027) and β-blocker use (OR: 17.12 [2.15–136.20], p = 0.007) were associated with higher E/SRe - a novel measure of left ventricular filling pressure. After backward elimination, only β-blocker use (OR: 17.22 [2.16, 137.14], p = 0.007) remained significant.ConclusionHigher GLS and E/SRe are common in ADPKD patients, even in patients with preserved eGFR and normal left ventricular EF. GLS and E/SRe may aid in cardiovascular risk stratification in patients with ADPKD as they represent early markers of cardiac dysfunction.

A Large Database Analysis of Rates of Aneurysm Screening, Elective Treatment, and Subarachnoid Hemorrhage in Patients With Polycystic Kidney Disease.

Professional societies provide conflicting guidelines on aneurysm screening in patients with polycystic kidney disease (PKD), and the rate of subarachnoid hemorrhage (SAH) is poorly understood. To evaluate screening, elective treatment, and the rate of SAH in patients with known PKD. We examined longitudinally linked claims data from a large private insurer, identifying screening, elective treatment, aneurysmal subarachnoid hemorrhage (aSAH) and secured aneurysmal SAH (saSAH) in 2004 to 2014 amongst patients with known PKD. We identified 20 704 patients diagnosed with PKD. Among patients with an initial PKD diagnosis, 51/446 (15.9%) underwent angiographic screening within 2 yr. Forty aneurysms were treated electively in 48 868 yr at risk in PKD patients (82/100K patient yr, 95% confidence interval [CI] 60-112) vs 24 elective treatments in 349 861 yr at risk in age- and sex-matched controls (7/100K patient yr, 95% CI 5-10, P<.0001). Eleven admissions for aSAH were identified in PKD patients (23/100K patient yr, 95% CI 13-41) and 22 admissions for aSAH in controls (6/100K patient yr, 95% CI 4-10), giving an incidence rate ratio (IRR) of 3.6 (95% CI 1.7-7.4, P<.0001) and a comorbidity-adjusted IRR of 3.1 (95% CI 1.4-6.9). The incidence of saSAH was proportionally even higher in PKD patients than controls, 16 vs 2/100K patient years, IRR 9.5 (95% CI 3.3-27.5, P<.0001). Screening in PKD is performed only selectively, though resulting rates of elective treatment were over 10× those of controls. Despite screening and treatment, the rate of SAH remains significantly elevated over that of controls.

SAT-331 RENAL DENERVATION DOES NOT REDUCE BLOOD PRESSURE IN A RODENT MODEL OF POLYCYSTIC KIDNEY DISEASE

Hypertension is a common, early feature of polycystic kidney disease (PKD) that contributes to the development of cardiovascular disease, a leading cause of mortality in these patients. Effective control of hypertension is therefore essential. Clinical trials show that renal denervation (RDN) can reduce blood pressure in hypertensive patients with chronic kidney disease, however, the impact of RDN on PKD patients as a specific cohort has not been examined. RDN involves surgical destruction of both the sympathetic and sensory components of the renal nerve, but which is responsible for any clinically relevant effects is not clear.

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.

Bilateral Nephrectomy for Adult Polycystic Kidney Disease Does Not Affect the Graft Function of Transplant Patients and Does Not Result in Sensitisation.

Background Native nephrectomy in Adult Polycystic Kidney Disease (ADPKD) patients is a major operation with controversy related to timing and indications. We present our single centre experience in transplanted patients and future candidates for transplantation. Methods Retrospective analysis from an anonymised database of bilateral nephrectomies for ADPKD patients. Results were reported as median, range, and percentage. Differences between groups were tested using ANOVA and t-test. Surgery was performed between January 2012 and July 2018. Results Thirty-three patients underwent bilateral native nephrectomy for APKD. 18 had a functioning kidney transplant (transplant group, 55%) while 15 patients were on dialysis (dialysis group, 45%) at the time of surgery; 8 patients of the latter group (24% of the whole cohort) were eventually transplanted. 53% were males, with median age of 55 years (27-71). Indications to surgery were the following: space (symptoms related to the size of the native kidneys or need to create space for transplantation) (59%), recurrent cyst infection (36%), haematuria (15%), pain (24%), and weight loss associated with cystic alteration on imaging (3%). In the transplant group, postoperative kidney function was not affected; haemoglobin serum levels significantly dropped in the whole cohort: 121 (82-150) g/L, versus 108 (58-154) g/L (p<0.001), with 14 patients being transfused perioperatively. Elevation of anti-HLA antibodies was noted in one female patient on dialysis, with no change in DSA levels and no rejection after transplant for all 26 transplanted patients. Median postoperative length of hospital stay was 9 days (6-71). One patient died (3%) after six months. Median follow-up for the whole cohort was 282 days (13-1834). Histopathological examination revealed incidental renal neoplasms in five cases (15%): 1 pT1a papillary renal cell carcinoma and 4 papillary adenomas. Conclusions Native nephrectomy for ADPKD could be safely performed in case of refractory symptoms, suspect of cancer or to create space for transplantation. It does not affect graft function or DSA status of transplanted patients or the prospect of transplantation of those on the waiting list.

Outcome of Autosomal Dominant Polycystic Kidney Disease Patients on Peritoneal Dialysis: a National Retrospective Study Based on Two French Registries (the French Language Peritoneal Dialysis Registry and the French Renal Epidemiology and Information Network).

Outcome of Autosomal Dominant Polycystic Kidney Disease Patients on Peritoneal Dialysis: a National Retrospective Study Based on Two French Registries (the French Language Peritoneal Dialysis Registry and the French Renal Epidemiology and Information Network).

Bialleleic PKD1 mutations underlie early-onset autosomal dominant polycystic kidney disease in Saudi Arabian families.

Polycystic kidney disease (PKD) is one of the most common genetic renal diseases and may be inherited in an autosomal dominant or autosomal recessive pattern. Pathogenic variants in two major genes, PKD1 and PKD2, and two rarer genes, GANAB and DNAJB11, cause autosomal dominant PKD (ADPKD). Early onset and severe PKD can occur with PKD1 and PKD2 pathogenic variants and such phenotypes may be modified by second alleles inherited in trans. Homozygous or compound heterozygous hypomorphic PKD1 variants may also cause a moderate to severe disease PKD phenotype. Targeted renal gene panel followed by Sanger sequencing of PKD1 gene were employed to investigate molecular causes in early onset PKD patients. In this study, we report four consanguineous Saudi Arabian families with early onset PKD which were associated with biallelic variants in PKD1 gene. Our findings confirm that PKD1 alleles may combine to produce severe paediatric onset PKD mimicking the more severe autosomal recessive ciliopathy syndromes associated with PKD. Screening of parents of such children may also reveal subclinical PKD phenotypes.

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.

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.

Serum klotho is inversely associated with metabolic syndrome in chronic kidney disease: results from the KNOW-CKD study

BackgroundMetabolic syndrome (MS) is prevalent in chronic kidney disease (CKD). Klotho, a protein linked to aging, is closely associated with CKD. Each component of MS and klotho has an association. However, little is known about the association between klotho and MS per se. We investigated the association between serum klotho levels and MS using baseline cross-sectional data obtained from a large Korean CKD cohort.MethodsOf the 2238 subjects recruited in the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD) between 2011 and 2016, 484 patients with missing data on serum klotho and extreme klotho values (values lower than the detectable range or > 6000 pg/mL) or with autosomal dominant polycystic kidney disease patients were excluded. The data of the remaining 1754 subjects were included in the present study. MS was defined using the revised National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP) III criteria. Serum klotho levels were measured using an enzyme-linked immunosorbent assay.ResultsMean patient age was 54.9 ± 12.1 years and 1110 (63.3%) were male. The prevalence of MS among all study subjects was 63.7% (n = 1118). The median serum klotho level was 527 pg/mL (interquartile range [IQR]: 418–656 pg/mL). Serum klotho level was significantly lower in MS patients than patients without MS (Median [IQR]; 521 pg/mL [413, 651] vs. 541 pg/mL [427, 676], respectively; P = 0.012). After adjusting for age, sex, estimated glomerular filtration rate, and overt proteinuria, serum klotho was independently associated with MS (adjusted odds ratio [OR], 0.44; 95% confidence interval, 0.23–0.82; P = 0.010). Furthermore, the adjusted OR for MS was found to be significantly increased at serum klotho levels of < 518 pg/mL (receiver operating characteristic curve cut-off value).ConclusionsSerum klotho was inversely associated with the presence of MS in patients with CKD.Trial registrationThis trial was registered on ClinicalTrials.gov on 26 June 2012 (https://clinicaltrials.gov;NCT01630486).

Factors influencing the clinical outcome of preimplantation genetic testing for polycystic kidney disease.

What are the factors influencing the success rate for couples undergoing preimplantation genetic testing (PGT) for polycystic kidney disease (PKD)? In our study cohort, the live birth delivery rate is significantly associated with female age while the male infertility accompanying autosomal dominant PKD (ADPKD) does not substantially affect the clinical outcome. While women with ADPKD have no specific fertility problems, male ADPKD patients may present with reproductive system abnormalities and infertility. This retrospective cohort study involves 91 PGT cycles for PKD for 43 couples (33 couples for PKD1, 2 couples for PKD2 and 8 couples for autosomal recessive PKD (ARPKD)) from January 2005 until December 2016 with follow-up of transfers until end of 2017. Sixteen single-cell clinical tests for PKD based on multiplex PCR of short tandem repeat markers, with or without a specific mutation were developed and applied for diagnosis of 584 Day 3 cleavage stage embryos. In 18 couples, the male partner was affected with ADPKD (=Group A) and 12 of them had a documented infertility status. Group A underwent 52 cycles to oocyte retrieval. For 18 other couples, the female partner was affected with ADPKD (=Group B) and four male partners from this group had a documented history of infertility. This group underwent 31 cycles to OR. Genetic analysis resulted in 545 embryos (93.3%) with a diagnosis, of which 215 (36.8%) were genetically transferable. Transfer of 74 embryos in 53 fresh cycles and of 34 cryopreserved embryos in 33 frozen-warmed embryo transfer cycles resulted in a live birth delivery rate of 38.4% per transfer with 31 singleton live births, two twin live births and one ongoing pregnancy. The observed cumulative delivery rate was 57.8% per couple after five treatment cycles. Thirty cryopreserved embryos still remain available for transfer. The clinical pregnancy rate per transfer (fresh + frozen; 45.9% in group A versus 60.0% in group B, P < 0.05) and the live birth delivery rate per transfer (fresh + frozen; 27.0% in group A versus 42.9% in group B, P < 0.05) was significantly lower for couples with the male partner affected with ADPKD compared with couples with the female partner affected with ADPKD. However, a multivariate logistic regression analysis showed that only female age was associated with live birth delivery rate (odds ratio = 0.87; 95% CI: 0.77-0.99; P = 0.032). This study is based on retrospective data from a single centre with Day 3 one-cell and two-cell biopsy. Further analysis of a larger cohort of PKD patients undergoing PGT is required to determine the impact of male infertility associated with ADPKD on the cumulative results. Knowledge about factors affecting the clinical outcome after PGT can be a valuable tool for physicians to counsel PKD patients about their reproductive options. Males affected with ADPKD who suffer from infertility should be advised to seek treatment in time to improve their chances of conceiving a child. No funding was obtained. There are no competing interests to declare. Not applicable.