scholarly journals A metabolomics approach using juvenile cystic mice to identify urinary biomarkers and altered pathways in polycystic kidney disease

2010 ◽  
Vol 298 (4) ◽  
pp. F909-F922 ◽  
Author(s):  
Sandra L. Taylor ◽  
Sheila Ganti ◽  
Nikolay O. Bukanov ◽  
Arlene Chapman ◽  
Oliver Fiehn ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Molecular Mechanisms ◽  
Kidney Diseases ◽  
Human Study ◽  
Cystic Kidney ◽  
Functional Score ◽  
Metabolomic Analysis ◽  
Polycystic Kidney ◽  
Diagnostic Potential

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and affects 1 in 1,000 individuals. Ultrasound is most often used to diagnose ADPKD; such a modality is only useful late in the disease after macroscopic cysts are present. There is accumulating evidence suggesting that there are common cellular and molecular mechanisms responsible for cystogenesis in human and murine PKD regardless of the genes mutated, and, in the case of complex metabolomic analysis, the use of a mouse model has distinct advantages for proof of principle over a human study. Therefore, in this study we utilized a urinary metabolomics-based investigation using gas chromatography-time of flight mass spectrometry to demonstrate that the cystic mouse can be discriminated from its wild-type counterpart by urine analysis alone. At day 26 of life, before there is serological evidence of kidney dysfunction, affected mice are distinguishable by urine metabolomic analysis; this finding persists through 45 days until 64 days, at which time body weight differences confound the results. Using functional score analysis and the KEGG pathway database, we identify several biologically relevant metabolic pathways which are altered very early in this disease, the most highly represented being the purine and galactose metabolism pathways. In addition, we identify several specific candidate biomarkers, including allantoic acid and adenosine, which are augmented in the urine of young cystic mice. These markers and pathway components, once extended to human disease, may prove useful as a noninvasive means of diagnosing cystic kidney diseases and to suggest novel therapeutic approaches. Thus, urine metabolomics has great diagnostic potential for cystic renal disorders and deserves further study.

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.

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.

Downregulation of Ke 6, a novel gene encoded within the major histocompatibility complex, in murine polycystic kidney disease

1993 ◽  
Vol 13 (3) ◽  
pp. 1847-1853
Author(s):  
N Aziz ◽  
M M Maxwell ◽  
B St Jacques ◽  
B M Brenner
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Kidney Diseases ◽  
Chromosome 17 ◽  
Cystic Kidney ◽  
Murine Models ◽  
Polycystic Kidney ◽  
Bacterial Proteins ◽  
Short Chain Alcohol ◽  
Cystic Kidney Diseases

Polycystic kidney disease (PKD) is characterized by progressive enlargement of the kidneys due to numerous expanding cysts ultimately leading to renal failure. We have identified a gene, Ke 6, located within the H-2K/tw5 region on mouse chromosome 17, which is downregulated in two distinct murine models of heritable PKD. Ke 6 is a member of the short-chain alcohol dehydrogenase family and possess remarkable amino acid sequence conservation with several bacterial proteins with oxidoreductase function. The Ke 6 gene gives rise to two transcripts--a 1-kb Ke 6a mRNA which is abundant in kidney and liver tissue and a 1.4-kb Ke 6b mRNA which is found at a moderate level in spleen tissue. We report here the complete nucleotide sequence of Ke 6a cDNA and the expression of the Ke 6 gene in murine models of PKD. The Ke 6 gene may be intimately involved in the manifestation of these cystic kidney diseases.

scholarly journals Reverse Phenotyping Maternal Cystic Kidney Disease by Diagnosis in a Newborn: Case Report and Literature Review on Neonatal Cystic Kidney Diseases

2021 ◽  
Vol 28 (2) ◽  
pp. 5
Author(s):  
Dovilė Ruzgienė ◽  
Meda Sutkevičiūtė ◽  
Birutė Burnytė ◽  
Kristina Grigalionienė ◽  
Augustina Jankauskienė
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Kidney Diseases ◽  
Pediatric Population ◽  
Genetic Disorders ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Polycystic Kidney ◽  
Kidney Cysts ◽  
Fetal Malformations

Kidney cysts are the most common kidney lesion, while congenital kidney cysts are mostly found in pediatric population. Neonatal kidney cysts can develop due to fetal malformations, rare genetic disorders or can be acquired which is very rare. Kidney cysts may be the only isolated finding or be part of the overall phenotype. They can be asymptomatic, found by ultrasound accidentally or can manifest from mild to life-threatening symptoms. Therefore, early diagnosis is very important. Autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease are the most common causes of kidney cysts in the neonatal population. This review highlights the most common kidney cystic diseases during the neonatal period and a rare clinical case of HNF1B-associated disease.

scholarly journals c-Jun N-terminal kinase (JNK) signaling contributes to cystic burden in polycystic kidney disease

PLoS Genetics ◽  
2021 ◽  
Vol 17 (12) ◽  
pp. e1009711
Author(s):  
Abigail O. Smith ◽  
Julie A. Jonassen ◽  
Kenley M. Preval ◽  
Roger J. Davis ◽  
Gregory J. Pazour
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Kidney Diseases ◽  
Cyst Formation ◽  
Cystic Kidney Disease ◽  
Nuclear Accumulation ◽  
Cystic Kidney ◽  
Polycystic Kidney ◽  
Jnk Pathway ◽  
Cystic Kidneys

Polycystic kidney disease is an inherited degenerative disease in which the uriniferous tubules are replaced by expanding fluid-filled cysts that ultimately destroy organ function. Autosomal dominant polycystic kidney disease (ADPKD) is the most common form, afflicting approximately 1 in 1,000 people. It primarily is caused by mutations in the transmembrane proteins polycystin-1 (Pkd1) and polycystin-2 (Pkd2). The most proximal effects of Pkd mutations leading to cyst formation are not known, but pro-proliferative signaling must be involved for the tubule epithelial cells to increase in number over time. The c-Jun N-terminal kinase (JNK) pathway promotes proliferation and is activated in acute and chronic kidney diseases. Using a mouse model of cystic kidney disease caused by Pkd2 loss, we observe JNK activation in cystic kidneys and observe increased nuclear phospho c-Jun in cystic epithelium. Genetic removal of Jnk1 and Jnk2 suppresses the nuclear accumulation of phospho c-Jun, reduces proliferation and reduces the severity of cystic disease. While Jnk1 and Jnk2 are thought to have largely overlapping functions, we find that Jnk1 loss is nearly as effective as the double loss of Jnk1 and Jnk2. Jnk pathway inhibitors are in development for neurodegeneration, cancer, and fibrotic diseases. Our work suggests that the JNK pathway should be explored as a therapeutic target for ADPKD.

scholarly journals c-Jun N-terminal kinase (JNK) signaling contributes to cystic burden in polycystic kidney disease

2021 ◽  
Author(s):  
Abigail O Smith ◽  
Julie A Jonassen ◽  
Kenley M Preval ◽  
Roger J Davis ◽  
Gregory J. Pazour
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Kidney Diseases ◽  
Cyst Formation ◽  
Cystic Kidney Disease ◽  
Nuclear Accumulation ◽  
Cystic Kidney ◽  
Polycystic Kidney ◽  
Jnk Pathway ◽  
Cystic Kidneys

Polycystic kidney disease is an inherited degenerative disease in which the uriniferous tubules are replaced by expanding fluid-filled cysts that ultimately destroy organ function. Autosomal dominant polycystic kidney disease (ADPKD) is the most common form, afflicting approximately 1 in 1,000 people. It primarily is caused by mutations in the transmembrane proteins polycystin-1 (Pkd1) and polycystin-2 (Pkd2). The most proximal effects of Pkd mutations leading to cyst formation are not known, but pro-proliferative signaling must be involved for the tubule epithelial cells to increase in number over time. The c-Jun N-terminal kinase (JNK) pathway promotes proliferation and is activated in acute and chronic kidney diseases. Using a mouse model of cystic kidney disease caused by Pkd2 loss, we observe JNK activation in cystic kidneys and observe increased nuclear phospho c-Jun in cystic epithelium. Genetic removal of Jnk1 and Jnk2 suppresses the nuclear accumulation of phospho c-Jun, reduces proliferation and reduces the severity of cystic disease. While Jnk1 and Jnk2 are thought to have largely overlapping functions, we find that Jnk1 loss is nearly as effective as the double loss of Jnk1 and Jnk2 . Jnk pathway inhibitors are in development for neurodegeneration, cancer, and fibrotic diseases. Our work suggests that the JNK pathway should be explored as a therapeutic target for ADPKD.

Systematic evaluation of olfaction in patients with hereditary cystic kidney diseases/renal ciliopathies

2020 ◽  
pp. jmedgenet-2020-107192
Author(s):  
Mareike Dahmer-Heath ◽  
Valentin Schriever ◽  
Sabine Kollmann ◽  
Carolin Schleithoff ◽  
Andrea Titieni ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Genetic Background ◽  
Kidney Diseases ◽  
Cystic Kidney ◽  
Molecular Defect ◽  
Polycystic Kidney ◽  
Sense Of Smell ◽  
Olfactory Deficit ◽  
Cystic Kidney Diseases

BackgroundHereditary cystic kidney diseases such as nephronophthisis, polycystic kidney disease and Bardet-Biedl syndrome (BBS) are caused by a dysfunction of primary cilia. Cilia are involved in a variety of cellular functions and perceptions, with one of them being the sense of smell. Hyposmia is a typical feature found in patients with BBS. However, reports of olfactory dysfunction in other cystic kidney diseases are sparse. Here we provide a systematic survey on olfaction in a large cohort of patients displaying genetically determined renal ciliopathies.MethodsWe performed a match-controlled systematic olfactory evaluation in a group of 75 patients with a defined genetic background using age adapted and validated odour identification tests.ResultsTest results revealed a significant olfactory deficit in patients carrying TMEM67 variants (n=4), while all other genetic disorders causing nephronophthisis (n=25) or polycystic kidney disease (n=18) were not associated with an impaired sense of smell. Also in patients with BBS, olfactory performance was depending on the underlying molecular defect. While defects in the BBS1 gene (n=9) had no impact on the sense of smell, all other BBS gene disorders (n=19) were associated with significant hyposmia. Noteworthy, there was no correlation of the olfactory deficit with the level of renal impairment.ConclusionHyposmia is a part of the clinical spectrum of BBS and of other renal ciliopathies. Depending on the genetic background, clinicians should be aware of this subtle and so far underappreciated symptom when clinically assessing patients with BBS or TMEM67 gene variants.

MO026CLINICAL AND MUTATIONAL SPECTRUM OF CHILDREN WITH AUTOSOMAL RECESSIVE AND AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Ozum Tutal ◽  
Bora Gulhan ◽  
Emine Atayar ◽  
Selcuk Yuksel ◽  
Z Birsin Ozcakar ◽  
...  
Keyword(s):  
Renal Transplantation ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Kidney Diseases ◽  
Cystic Kidney ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cystic Kidney Diseases ◽  
Pkd2 Mutation

Abstract Background and Aims Cystic kidney diseases are a heterogeneous group of chronic renal disease. Autosomal recessive polycystic kidney disease (ARPKD) is generally diagnosed in utero or at birth due to mutations in PKHD1 gene. Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease commonly associated with mutations in PKD1 or PKD2. In this study, we aimed to investigate clinical and genetic features of ARPKD and ADPKD in a group of Turkish patients. Method A total of 69 children with genetically confirmed ARPKD (10 females, 11 males) or ADPKD (28 females, 20 males) from seven pediatric nephrology centers were included in this study. Demographic features, family history, clinical and laboratory findings at presentation and during 12 months intervals were collected. Results For ARPKD patients, the median age at diagnosis was 10.5 (IQR; 0.75-58.5) months. Consanguinity between parents was present in 11 patients (52.4%). At the time of diagnosis, 14 (66.7%) patients had eGFR&lt;90 ml/min/1.73 m2. Mean duration of follow-up was 4.1±3,7 years. At the last visit, median eGFR was 74 (IQR; 43-126) ml/min/1.73m2. A total of 6 patients (28,6%) underwent a renal replacement therapy (RRT), 3 of them died in infancy and 2 of them had renal transplantation during follow up. All patients had bi-allelic PKHD1 mutation. For ADPKD patients, the mean age at diagnosis was 5.5±4.6 years. At the time of diagnosis 11 (22.9%) patients had eGFR&lt;90 ml/min/1.73m2. Mean duration of follow-up was 2,7±2.3 years. At the last visit, median eGFR was 114 (IQR; 98-135) ml/min/1.73m2. Only one patient underwent a renal transplantation. A total of 42 patients (87.5%) had a heterozygous PKD1 mutation while 6 (12.5%) had a heterozygous PKD2 mutation. The rate of growth retardation, hypertension at diagnosis and progression to chronic kidney disease (CKD) were higher in patients with PKHD1 mutation than the patients with PKD1 or PKD2 mutation (p &lt; 0.001, p &lt; 0.001 and p = 0.001, respectively). In kidney survival analysis, mutation type, growth retardation at presentation, increased renal echogenity in ultrasonography were found as independent risk factors for progression to CKD. Conclusion Cystic kidney diseases are one of the most clinically and genetically heterogenous diseases. Differentiating them and establishing the predictors for CKD development is important to provide appropriate management including choosing appropriate donor in renal transplantation.

scholarly journals Downregulation of Ke 6, a novel gene encoded within the major histocompatibility complex, in murine polycystic kidney disease.

1993 ◽  
Vol 13 (3) ◽  
pp. 1847-1853 ◽  
Author(s):  
N Aziz ◽  
M M Maxwell ◽  
B St Jacques ◽  
B M Brenner
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Kidney Diseases ◽  
Chromosome 17 ◽  
Cystic Kidney ◽  
Murine Models ◽  
Polycystic Kidney ◽  
Bacterial Proteins ◽  
Short Chain Alcohol ◽  
Cystic Kidney Diseases

Polycystic kidney disease (PKD) is characterized by progressive enlargement of the kidneys due to numerous expanding cysts ultimately leading to renal failure. We have identified a gene, Ke 6, located within the H-2K/tw5 region on mouse chromosome 17, which is downregulated in two distinct murine models of heritable PKD. Ke 6 is a member of the short-chain alcohol dehydrogenase family and possess remarkable amino acid sequence conservation with several bacterial proteins with oxidoreductase function. The Ke 6 gene gives rise to two transcripts--a 1-kb Ke 6a mRNA which is abundant in kidney and liver tissue and a 1.4-kb Ke 6b mRNA which is found at a moderate level in spleen tissue. We report here the complete nucleotide sequence of Ke 6a cDNA and the expression of the Ke 6 gene in murine models of PKD. The Ke 6 gene may be intimately involved in the manifestation of these cystic kidney diseases.

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