POLYMORPHISM OF STAT4, PTPN22, VEGF, TGF-B, PDCD1 AND PD-L1 GENES IN CHILDREN WITH HEREDITARY NEPHRITIS AND POLYCYSTIC KIDNEY DISEASE

2021 ◽  
pp. 49-55
Author(s):  
A. G. Bialkevich ◽  
◽  
A. V. Sukalo ◽  
I. A. Kazyra ◽  
N. V. Nikitchenko ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Kidney Diseases ◽  
Polymorphic Locus ◽  
Minor Allele ◽  
Control Group ◽  
Polycystic Kidney ◽  
Hereditary Nephritis ◽  
Treatment And Prevention ◽  
Genotype Frequencies

The study of the molecular and genetic nature of inherited kidney diseases is relevant in modern nephrology. It allows us to establish the etiology, develop new methods of treatment and prevention. The aim of the research was to study the genetic polymorphism of STAT4, PTPN22, VEGF, TGF-B, PDCD1 and PD-L1 in children with hereditary kidney diseases. The study included patients with hereditary nephritis (n = 40), polycystic kidney disease (n = 26) and chil dren without kidney diseases (n = 416). We use a standard method of phenol-chloroform extraction to isolate genomic DNA. Polymorphic variants of genes were determined using such methods of polymerase chain reaction (PCR) as estriction fragment length polymorphism PCR and real-time PCR. Genotyping of polymorphic of loci rs7574865 and rs 3821236 of the STAT4 gene in the group of patients with polycystic kidney disease compared with the control was observed significant differences in genotype frequencies in boys. The development of polycystic kidney disease is associated with the presence of genotypes GT + TT and minor allele T of the polymorphic locus rs7574865 of the STAT4 gene and genotypes GA + AA and allele A of the polymorphic locus rs3821236 of the STAT4 gene which is especially pronounced in groups of male patients. Analysis of the frequency distribution of genotypes/alleles in the boys confirmed a significant association of the CC genotype and the minor allele C of polymorphic locus rs2297136 of the PD-L1 gene with the risk of development of hereditary nephritis. The frequencies of genotypes/alleles of the polymorphic loci of PTPN22 rs2476601, TGF-B rs1800469, PDCD1 rs11568821 and VEGF rs699947, rs2010963 in children with hereditary nephritis and polycystic kidney disease didn't significantly differ from the similar indicators in the control group.

MO046NGS PANEL PERFORMANCE IN THE DIAGNOSIS OF HEREDITARY RENAL DISEASE IN SOUTHERN SPAIN

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
María del Mar Del Águila García ◽  
Antonio M Poyatos Andújar ◽  
Ana Isabel Morales García ◽  
Margarita Martínez Atienza ◽  
Susana García Linares ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Renal Disease ◽  
Polycystic Kidney Disease ◽  
Genetic Study ◽  
Alport Syndrome ◽  
Autosomal Dominant ◽  
Kidney Diseases ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
Hereditary Renal Disease

Abstract Background and Aims Hereditary renal disease (HRD) is still underdiagnosed: although we know aspects related to autosomal dominant polycystic kidney disease (ADPKD), we know little about the incidence and prevalence of other entities such as Alport syndrome. Altogether, HRD can represent 15% of individuals undergoing renal replacement therapy (RRT) or could even be higher. The advancement of genetics at the healthcare level let to achieve accurate and early renal diagnoses, as well as the incorporation of genetic counseling to families, all of which will result in better management of the disease in its initial stages and the possibility of offering reproductive options that avoid transmission to offspring. Our objective is to know the performance offered by the implementation of the ERH panel through Next Generation Sequencing (NGS) in our healthcare area. Method Observational-descriptive study of 259 probands (141 men / 118 women), mean age of 46 years (30 pediatric / 123 over 50 years), with chronic kidney disease and suspected hereditary cause attended in the specialized consultation of our centers from October 2018 to October 2020. The DNA extracted from leukocytes obtained by venipuncture was processed with Nephropathies Solution version 3 panel (SOPHiA Genetics) according to the manufacturer's protocol. This panel covers the coding regions and splicing junctions of 44 HRD-related genes such as nephrotic syndromes, polycystic kidney diseases, Bartter syndromes, Alport syndrome, CAKUT or tubulopathies (table 1). The sequencing of the libraries was done in a MiSeq (Illumina Inc), the bioinformatic analysis of the data and annotation of variants was performed using the SOPHiA DDM 5.8.0.3 software, and the revision of variants by consulting the main databases (ClinVar, Exac, HGMD, NCBI, PKD Foundation, LOVD). Results The panel was informative (pathogenic or probably pathogenic) in 80/259 patients (31%) and 56/259 cases (21.66%) of variants of uncertain significance (VSI) were detected. Autosomal dominant polycystic kidney disease accounted for 76.2% of the variants identified (56.2% PKD1, 20% PKD2), following Alport syndrome with 15% and the alterations in the PKHD1 gene associated with renal polycystic disease in its recessive form with about 4% (Figure 1). We have also identified a case of autosomal dominant tubulointerstitial kidney disease associated with the UMOD gene that was not suspected until the genetic study was performed. We highlight that 45% (36/80) of the variants identified as responsible for the renal disease are not yet described. Overall, the most prevalent type of mutation is that which produces displacement in the reading frame or frameshift (Figure 2). Individually, frameshift is the most frequent alteration in PKD1, PKD2 and COL4A5, while for PKHD1, COL4A3 and COL4A4 it is missense. Conclusion Our NGS HRD panel a) offers an adequate diagnostic performance at the healthcare level, with definitive results in 1 out of 3 cases and has also allowed the performance of many carrier studies among family members b) is able of diagnosing the most frequent disease, ADPKD and Alport syndrome, as well as unresolved or poorly characterized cases, and c) opens the horizon for new diagnoses, all without increasing costs by outsourcing services. All this makes the genetic study of renal pathology a useful and efficient strategy. These results encourage us to enhance the resources in this area that we consider to be of strategic value.

scholarly journals Hypomagnesaemia is absent in children with autosomal dominant polycystic kidney disease

2018 ◽  
Vol 56 (1) ◽  
pp. 90-94 ◽  
Author(s):  
Tomáš Seeman ◽  
Magdaléna Fořtová ◽  
Bruno Sopko ◽  
Richard Průša ◽  
Michael Pohl ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Kidney Diseases ◽  
Differential Diagnostics ◽  
Cystic Kidney ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cystic Kidney Diseases ◽  
Rule Out

Background Hypomagnesaemia is present in 40–50% of children with autosomal dominant renal cysts and diabetes syndrome (RCAD). On the contrary, the prevalence of hypomagnesaemia in children with autosomal dominant polycystic kidney disease (ADPKD) has never been examined. We aimed to investigate whether hypomagnesaemia is present in children with polycystic kidney diseases. Methods Children with cystic kidney diseases were investigated in a cross-sectional study. Serum concentrations of magnesium (S-Mg) and fractional excretion of magnesium (FE-Mg) were tested. Fifty-four children with ADPKD ( n = 26), autosomal recessive polycystic kidney disease (ARPKD) ( n = 16) and RCAD ( n = 12) with median age of 11.2 (0.6–18.6) years were investigated. Results Hypomagnesaemia (S-Mg < 0.7 mmol/L) was detected in none of the children with ADPKD/ARPKD and in eight children (67%) with RCAD. Median S-Mg in children with ADPKD/ARPKD was significantly higher than in children with RCAD (0.89 vs. 0.65 mmol/L, P < 0.01). The FE-Mg was increased in 23% of patients with ADPKD/ARPKD (all had chronic kidney disease stages 2–4) and in 63% of patients with RCAD, where it significantly correlated with estimated glomerular filtration rate (r = −0.87, P < 0.01). Conclusions Hypomagnesaemia is absent in children with ADPKD or ARPKD and could serve as a marker for differential diagnostics between ADPKD, ARPKD and RCAD in children with cystic kidney diseases of unknown origin where molecular genetic testing is lacking. However, while hypomagnesaemia, in the absence of diuretics, appears to rule out ADPKD and ARPKD, normomagnesaemia does not rule out RCAD at least in those aged <3 years.

scholarly journals Effect of Statins on Renal Function and Total Kidney Volume in Autosomal Dominant Polycystic Kidney Disease

2020 ◽  
Vol 6 (6) ◽  
pp. 407-413
Author(s):  
Cheng Xue ◽  
Li-Ming Zhang ◽  
Chenchen Zhou ◽  
Chang-Lin Mei ◽  
Sheng-Qiang Yu
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Lipid Lowering ◽  
Control Group ◽  
Kidney Volume ◽  
Polycystic Kidney ◽  
Total Kidney Volume ◽  
Yearly Change ◽  
Autosomal Dominant Polycystic Kidney

<b><i>Background:</i></b> Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary nephropathy with few treatments to slow renal progression. The evidence on the effect of lipid-lowering agents (statins) on ADPKD progression remains inconclusive. <b><i>Methods:</i></b> We performed a systematic review and meta-analysis by searching the PubMed, Embase, Web of Science, and Cochrane databases (up to November 2019). Changes in estimated glomerular filtration rate (eGFR) and total kidney volume (TKV) were the primary outcomes. Mean differences (MDs) for continuous outcomes and 95% confidence intervals (CIs) were calculated by a random-effects model. <b><i>Results:</i></b> Five clinical studies with 648 participants were included. Statins did not show significant benefits in the yearly change in eGFR (4 studies, MD = −0.13 mL/min/m<sup>2</sup>, 95% CI: −0.78 to 0.52, <i>p</i> = 0.70) and the yearly change in TKV (3 studies, MD = −1.17%, 95% CI: −3.40 to 1.05, <i>p</i> = 0.30) compared with the control group. However, statins significantly decreased urinary protein excretion (−0.10 g/day, 95% CI: −0.16 to -0.03, <i>p</i> = 0.004) and serum low-density lipoprotein level (−0.34 mmol/L, 95% CI: −0.58 to −0.10, <i>p</i> = 0.006). <b><i>Conclusion:</i></b> Despite these proteinuria and lipid-lowering benefits, the effect of statins on ADPKD progression was uncertain.

A Sphingosine-1-Phosphate Modulator Ameliorates Polycystic Kidney Disease in Han:SPRD Rats

2019 ◽  
Vol 51 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Xin Li ◽  
Ming Wu ◽  
Limin Chen ◽  
Junyan Lu ◽  
Guo Li ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Inflammatory Cytokines ◽  
Inflammatory Responses ◽  
Kidney Diseases ◽  
Cordyceps Sinensis ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Polycystic Kidney ◽  
Sphingosine 1 Phosphate

Background: Inflammation plays an important role in polycystic kidney disease (PKD). Cordyceps sinensis, a prized ­Chinese medicinal herb, exerts anti-tumor, anti-inflammatory and anti-metastatic effects and benefits patients with kidney diseases. The aim of this study was to test the efficacy of FTY720, an immunosuppressant derived from C. sinensis, in a rat cystic kidney disease model, and explore its underlining mechanism. Methods: Male wild type and Cy/+ Han:SPRD rats were treated with FTY720 at 3 and 10 mg/kg/day for 5 weeks and 12 weeks by gavage. Blood and kidney were collected for functional, morphological, RNA, and protein analysis. Results: Inflammation is activated in Cy/+ Han:SPRD rats. Inflammatory cytokines including interleukin 6 and tumor necrosis factor alpha were upregulated and inflammation-related pathways were activated, such as nuclear factor κB and signal transducer and activator of transcription 3 (STAT3) pathways. Furthermore, the bioactive sphingolipid mediator sphingosine-1-phosphate (S1P), a regulator of inflammation, was accumulated in the Cy/+ Han:SPRD rats. FTY720 significantly reduced cyst growth and delayed disease progression by reducing the accumulation of S1P, thereby inhibiting inflammatory responses. Conclusion: FTY720 treatment reduced the expression of inflammatory cytokines and attenuated the activation of NK-κB and STAT3 pathways in Cy/+ Han:SPRD rats. It suggests that FTY720 may serve as a therapeutic agent for clinical autosomal dominant PKD treatment.

scholarly journals Severe neurological outcomes after very early bilateral nephrectomies in patients with autosomal recessive polycystic kidney disease (ARPKD)

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Kathrin Burgmaier ◽  
◽  
Gema Ariceta ◽  
Martin Bald ◽  
Anja Katrin Buescher ◽  
...  
Keyword(s):  
Risk Factors ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Neurological Complications ◽  
Control Group ◽  
Polycystic Kidney ◽  
Neurological Outcomes ◽  
Additional Control ◽  
Independent Risk Factors

Abstract To test the association between bilateral nephrectomies in patients with autosomal recessive polycystic kidney disease (ARPKD) and long-term clinical outcome and to identify risk factors for severe outcomes, a dataset comprising 504 patients from the international registry study ARegPKD was analyzed for characteristics and complications of patients with very early (≤ 3 months; VEBNE) and early (4–15 months; EBNE) bilateral nephrectomies. Patients with very early dialysis (VED, onset ≤ 3 months) without bilateral nephrectomies and patients with total kidney volumes (TKV) comparable to VEBNE infants served as additional control groups. We identified 19 children with VEBNE, 9 with EBNE, 12 with VED and 11 in the TKV control group. VEBNE patients suffered more frequently from severe neurological complications in comparison to all control patients. Very early bilateral nephrectomies and documentation of severe hypotensive episodes were independent risk factors for severe neurological complications. Bilateral nephrectomies within the first 3 months of life are associated with a risk of severe neurological complications later in life. Our data support a very cautious indication of very early bilateral nephrectomies in ARPKD, especially in patients with residual kidney function, and emphasize the importance of avoiding severe hypotensive episodes in this at-risk cohort.

Do metabolic derangements in end-stage polycystic kidney disease differ versus other primary kidney diseases?

Nephrology ◽  
2017 ◽  
Vol 23 (1) ◽  
pp. 31-36 ◽  
Author(s):  
Magdalena Jankowska ◽  
Abdul Rashid Qureshi ◽  
Peter Barany ◽  
Olof Heimburger ◽  
Peter Stenvinkel ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Kidney Diseases ◽  
Polycystic Kidney ◽  
End Stage

scholarly journals Exploring the Spectrum of Kidney Ciliopathies

Diagnostics ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1099
Author(s):  
Matteo Santoni ◽  
Francesco Piva ◽  
Alessia Cimadamore ◽  
Matteo Giulietti ◽  
Nicola Battelli ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Signaling Pathways ◽  
Polycystic Kidney Disease ◽  
Primary Cilium ◽  
Primary Cilia ◽  
Kidney Diseases ◽  
Ubiquitin Proteasome System ◽  
Polycystic Kidney ◽  
Ubiquitin Proteasome ◽  
Autosomal Dominant Polycystic Kidney

Ciliopathies are a group of multi-organ diseases caused by the disruption of the primary cilium. This event leads to a variety of kidney disorders, including nephronophthisis, renal cystic dysplasia, and renal cell carcinoma (RCC). Primary cilium contributes to the regulation of the cell cycle and protein homeostasis, that is, the balance between protein synthesis and degradation by acting on the ubiquitin-proteasome system, autophagy, and mTOR signaling. Many proteins are involved in renal ciliopathies. In particular, fibrocystin (PKHD1) is involved in autosomal recessive polycystic kidney disease (ARPKD), while polycystin-1 (PKD1) and polycystin-2 (PKD2) are implicated in autosomal dominant polycystic kidney disease (ADPKD). Moreover, primary cilia are associated with essential signaling pathways, such as Hedgehog, Wnt, and Platelet-Derived Growth Factor (PDGF). In this review, we focused on the ciliopathies associated with kidney diseases, exploring genes and signaling pathways associated with primary cilium and the potential role of cilia as therapeutic targets in renal disorders.

MO1005ADPEDKD: A GLOBAL ONLINE PLATFORM TO EXPLORE THE CHILDHOOD PHENOTYPE OF AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE*

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Angélique Dachy ◽  
Stéphanie De Rechter ◽  
Lisa Guay-Woodford ◽  
Andrew John Mallett ◽  
Tess Harris ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Longitudinal Data ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Kidney Diseases ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
Tract Infections ◽  
Prospective Longitudinal

Abstract Background and Aims Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the 4th common cause of renal replacement therapy worldwide. As the disorder has been historically considered an adult-onset disease, there is a lack of longitudinal data from large pediatric cohorts. However, evidence is growing that first manifestations of ADPKD may be detected in childhood and children represent a specific target population for future treatment, allowing a better chance of preserving long term kidney function. To better define the pediatric spectrum of the disease, a global multicenter observational study on childhood-diagnosed ADPKD was launched in 2017. Method The ADPedKD registry is a worldwide web-based database, including both retrospective and prospective longitudinal data from young ADPKD patients (≤19 years). Australia, North-America and the United Kingdom joined the initiative with their source databases, namely the KidGen Collaborative (KidGen), NIH-funded Hepato-Renal Fibrocystic Disease (HRFD) and National Registry of Rare Kidney Diseases (RaDaR). Under informed consent, de-identified patient data, including genetics, radiological and laboratory findings, treatments and follow-up were enrolled in the database accessible via https://www.ADPedKd.org/. Results 1019 ADPKD children (from 89 centers and 33 countries) are enrolled in the registry of which 167 patients from RaDaR, 17 from KidGen, 11 from HRFD and 824 from ADPedKD (401 male/ 423 female) with a mean (± SD) age at diagnosis of 6.3 ± 5.2 years. 81 children (9.8%) were diagnosed prenatally at a mean gestational age of 26.8 ± 7.8 weeks. Reasons for initial visit were: family screening in 325 (39.4%), postnatal incidental finding in 223 (27.0%), presenting features (such as hematuria, hypertension, urinary tract infections and flank or back pain) in 150 (18.2%) or unknown/not available in 126 (15.3%). Genetic testing was performed in 42.8% of the population, with the following results: PKD1 mutation (85.4%), PKD2 mutation (11.7%) and others (6.0%). Conclusion The ADPedKD registry is a unique source of clinical observational data that will provide deep phenotyping of children with ADPKD and will allow to define unified diagnostic, treatment and follow-up recommendations.

MO044TARGETED NEXT GENERATION SEQUENCING AND MULTIDISCIPLINARY APPROACH IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE, ALPORT DISEASE AND FAMILIAL HAEMATURIA: GENETIC SPECTRUM AND CLINICAL UTILITY IN A SPANISH COHORT

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Isabel Galan Carrillo ◽  
Liliana Galbis ◽  
Víctor Martínez Jiménez ◽  
Juan David Castro ◽  
Fernanda Ramos ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Clinical Utility ◽  
Multidisciplinary Approach ◽  
Kidney Biopsy ◽  
Kidney Diseases ◽  
Polycystic Kidney ◽  
Pathogenic Variants ◽  
Generation Sequencing

Abstract Background and Aims Autosomal Polycystic kidney Disease (ADPKD; ORPHA 730), Alport Syndrome (AS; ORPHA 63) and Familial Haematuria (FH) are the most frequent inherited kidney diseases. Next-generation Sequencing (NGS) has facilitated their molecular identification. A multidisciplinary team from four hospitals, with nephrologists, pediatricians, and clinical and molecular geneticists, has been formed in the Spanish region of Murcia (1.5 million inhabitants) with the lab implementation of NGS. Our aim is to evaluate the genetic spectrum in AS, FH and ADPKD and the clinical utility of this comprehensive approach. Method During 1-year activity, 114 individuals with diagnostic suspicion of ADPKD, AS or FH have been evaluated by a coordinated clinical protocol with periodic cases discussions. A customized Agilent panel was designed to capture 113 genes associated with several genetic diseases, including some related to PKD, AS or Familial Haematuria (FH): PKD1, PKD2, PKHD1, HNF1β, COL4A1, COL4A3, COL4A4 and COL4A5. Interpretation of sequence variants was performed according to the American College of Medical Genetics and Genomics (ACMG) Guidelines. Sanger sequencing was performed to confirm variants identified by NGS and to segregate them in the families. Exon 1 of PKD1 gene was also sequenced by Sanger method, due to the suboptimal capture of this region by NGS. Results We detected genetic variants in 63 patients (55.3%), pathogenic or probably pathogenic variants in 54 (47.8%). 31 patients had a variant in AS associated genes: 10 in COL4A3, 18 in COL4A4, 2 in COL4A1 and 1 in COL4A5. There were 13 pathogenic variants, 12 probably pathogenic variants and 6 variants of uncertain clinical significance (VUCS). Among them, 27 had an AD inheritance, 1 AR and 3 were sporadic. All the patients with any variant had microhaematuria, a 68% had also proteinuria, and mean eGFR at diagnostic was 63.79±21 ml/min/1.73m2. 61% had auditory disturbances and 11% ophthalmologic alterations. 4 of them had underwent kidney biopsy previously, but 3 were not adequately diagnosed, so they were reclassified after the molecular diagnosis. In total, 16 kidney biopsies were avoided by the genetic diagnosis. On the other hand, 29 patients had a variant in the ADPKD associated genes: 24 in PKD1 and 5 in PKD2. There were 20 pathogenic variants and 4 probably pathogenic variants, and their inheritance was confirmed AD in 27 patients, whereas new sporadic mutations were identified in 2 patients. 22 patients had big or enormous kidneys on sonography, although 7 had normal size. Hepatic cysts were present on 5%. 19 patients had hypertension, with a mean age of diagnosis of 47±14 years. Additionally, 1 patient was diagnosed on AR polycystic disease with homozygosity PKHD1 pathogenic variant. Among all the scope, familial history was clearly present in 43 patients, uncertain in 11, and not present in 9 patients. Conclusion The multidisciplinary approach to hereditary kidney diseases, with the active participation of nephrologists and clinical geneticists, has allowed a molecular diagnostic yield of 48% among patients with AS and ADPKD, employing NGS technology. This has led to a quicker diagnostic result in our region, the reclassification of some patient’s diagnosis, a decrease in invasive diagnostic procedures (such as kidney biopsy) and the correspondent adverse events and cost savings. Additionally, the AD inheritance pattern in AS has been confirmed as the most frequent in the region. The active participation of nephrologists in genomic medicine teams results in a better characterization of the hereditary kidney diseases, helping in the genetic variant interpretation and management of these patients and their families.

Sign in / Sign up

Export Citation Format

Share Document