scholarly journals Association between urinary biomarkers and disease progression in adults with autosomal dominant polycystic kidney disease

2019 ◽  
Vol 13 (4) ◽  
pp. 607-612
Author(s):  
Alfons Segarra-Medrano ◽  
Marisa Martin ◽  
Irene Agraz ◽  
Mercè Vilaprinyó ◽  
Betty Chamoun ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Kidney Function ◽  
Autosomal Dominant ◽  
Kidney Injury ◽  
Polycystic Kidney ◽  
Β2 Microglobulin ◽  
Urinary Levels ◽  
Autosomal Dominant Polycystic Kidney ◽  
Egfr Slope

Abstract Background Height-adjusted total kidney volume (htTKV) is considered as the best predictor of kidney function in patients with autosomal dominant polycystic kidney disease (ADPKD), but its limited predictive capacity stresses the need to find new biomarkers of ADPKD progression. The aim of this study was to investigate urinary biomarkers of ADPKD progression. Methods This observational study included ADPKD patients, and two comparator groups of ischaemic and non-ischaemic kidney injury: benign nephroangiosclerosis patients and non-ischaemic chronic kidney disease (CKD) patients. Proteinuria, htTKV and urinary levels of molecules are associated with ischaemia and/or tubular injury. The slope of estimated glomerular filtration rate (eGFR) was used as a dependent variable in univariate and multivariate models of kidney function decline. Results The study included 130 patients with ADPKD, 55 with nephroangiosclerosis and 40 with non-ischaemic CKD. All patients had increased urinary concentrations of biomarkers associated with tubular lesions (liver fatty acid-binding protein, kidney injury molecule-1, β2-microglobulin) and molecules overexpressed under ischaemic conditions [hypoxia-inducible factor-1α, vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1)]. These biomarkers correlated positively with htTKV and negatively with the eGFR slope. htTKV was the single best predictor of the eGFR slope variability in univariate analyses. However, a multivariate model including urinary levels of β2-microglobulin, MCP-1 and VEGF improved the capacity to predict the decline of eGFR in ADPKD patients compared with htTKV alone. Conclusions The urinary levels of molecules associated with either renal ischaemia (VEGF and MCP-1) or tubular damage (β2-microglobulin) are associated with renal function deterioration in ADPKD patients, and are, therefore, candidates as biomarkers of ADPKD progression.

scholarly journals A study of sirolimus and mTOR kinase inhibitor in a hypomorphic Pkd1 mouse model of autosomal dominant polycystic kidney disease

2019 ◽  
Vol 317 (1) ◽  
pp. F187-F196 ◽  
Author(s):  
Sara J. Holditch ◽  
Carolyn N. Brown ◽  
Daniel J. Atwood ◽  
Andrew M. Lombardi ◽  
Khoa N. Nguyen ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mouse Model ◽  
Polycystic Kidney Disease ◽  
Kidney Function ◽  
Autosomal Dominant ◽  
Kinase Inhibitor ◽  
Polycystic Kidney ◽  
Mtor Kinase ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

Autosomal dominant polycystic kidney disease (PKD) is characterized by cyst formation and growth, which are partially driven by abnormal proliferation of tubular cells. Proproliferative mechanistic target of rapamycin (mTOR) complexes 1 and 2 (mTORC1 and mTORC2) are activated in the kidneys of mice with PKD. Sirolimus indirectly inhibits mTORC1. Novel mTOR kinase inhibitors directly inhibit mTOR kinase, resulting in the inhibition of mTORC1 and mTORC2. The aim of the present study was to determine the effects of sirolimus versus the mTOR kinase inhibitor torin2 on cyst growth and kidney function in the Pkd1 p.R3277C ( Pkd1RC/RC) mouse model, a hypomorphic Pkd1 model orthologous to the human condition, and to determine the effects of sirolimus versus torin2 on mTORC1 and mTORC2 signaling in PKD1−/− cells and in the kidneys of Pkd1RC/RC mice. In vitro, both inhibitors reduced mTORC1 and mTORC2 phosphorylated substrates and negatively impacted cellular metabolic activity, as measured by MTT assay. Pkd1RC/RC mice were treated with sirolimus or torin2 from 50 to 120 days of age. Torin2 was as effective as sirolimus in decreasing cyst growth and improving loss of kidney function. Both sirolimus and torin2 decreased phosphorylated S6 protein, phosphorylated eukaryotic translation initiation factor 4E-binding protein 1, phosphorylated Akt, and proliferation in Pkd1RC/RC kidneys. In conclusion, torin2 and sirolimus were equally effective in decreasing cyst burden and improving kidney function and mediated comparable effects on mTORC1 and mTORC2 signaling and proliferation in the Pkd1RC/RC kidney.

scholarly journals Long-term trajectory of kidney function in autosomal-dominant polycystic kidney disease

2019 ◽  
Vol 95 (5) ◽  
pp. 1253-1261 ◽  
Author(s):  
Alan S.L. Yu ◽  
Chengli Shen ◽  
Douglas P. Landsittel ◽  
Jared J. Grantham ◽  
Larry T. Cook ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Kidney Function ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney

scholarly journals Urinary metabolites associate with the rate of kidney function decline in patients with autosomal dominant polycystic kidney disease

PLoS ONE ◽  
2020 ◽  
Vol 15 (5) ◽  
pp. e0233213 ◽  
Author(s):  
Shosha E. I. Dekker ◽  
Aswin Verhoeven ◽  
Darius Soonawala ◽  
Dorien J. M. Peters ◽  
Johan W. de Fijter ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Kidney Function ◽  
Autosomal Dominant ◽  
Urinary Metabolites ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
Kidney Function Decline

scholarly journals Kidney Function and Plasma Copeptin Levels in Healthy Kidney Donors and Autosomal Dominant Polycystic Kidney Disease Patients

2014 ◽  
Vol 9 (9) ◽  
pp. 1553-1562 ◽  
Author(s):  
Debbie Zittema ◽  
Else van den Berg ◽  
Esther Meijer ◽  
Wendy E. Boertien ◽  
Anneke C. Muller Kobold ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Kidney Function ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Kidney Donors ◽  
Autosomal Dominant Polycystic Kidney

scholarly journals Metformin Improves Relevant Disease Parameters in an Autosomal Dominant Polycystic Kidney Disease Mouse Model

2021 ◽  
Author(s):  
Nuria M Pastor-Soler ◽  
Hui Li ◽  
Jessica Pham ◽  
Daniel Rivera ◽  
Pei-Yin Ho ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mouse Model ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Severe Disease ◽  
Treatment Options ◽  
Kidney Injury ◽  
Polycystic Kidney ◽  
Gene And Protein Expression ◽  
Autosomal Dominant Polycystic Kidney

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in the PKD1 or PKD2 genes encoding polycystins, presents with progressive development of kidney cysts and eventual end-stage kidney disease (ESKD) with limited treatment options. Previous work showed that metformin reduces cyst growth in rapid ADPKD mouse models via inhibition of CFTR-mediated fluid secretion, mTOR, and cAMP pathways. The present study importantly tested the effectiveness of metformin as a therapy for ADPKD in a more clinically relevant Pkd1RC/RC mouse model, homozygous for the R3277C knock-in point mutation in the Pkd1 gene. This mutation causes ADPKD in humans. Pkd1RC/RC male and female mice, which have slow progression to ESKD, received metformin (300 mg/kg/day in drinking water vs. water alone) from 3 to 9 or 12 months of age. As previously reported, Pkd1RC/RC females had a more severe disease phenotype than males. Metformin treatment reduced the ratio of total kidney weight to body weight relative to age- and sex-matched untreated controls at both 9 and 12 months and reduced cystic index in females at 9 months. Metformin also increased glomerular filtration rate (GFR), lowered systolic blood pressure, improved anemia, and lowered blood urea nitrogen levels relative to controls in both sexes. Moreover, metformin reduced gene expression of key inflammatory markers and both gene and protein expression of kidney injury marker-1 and cyclin-dependent kinase-1 vs. untreated controls. Altogether, these findings suggest several beneficial effects of metformin in this highly relevant slowly progressive ADPKD mouse model, which may help inform new ADPKD therapies in patients.

scholarly journals Effect of Lanreotide on Kidney Function in Patients With Autosomal Dominant Polycystic Kidney Disease

JAMA ◽  
2018 ◽  
Vol 320 (19) ◽  
pp. 2010 ◽  
Author(s):  
Esther Meijer ◽  
Folkert W. Visser ◽  
Rene M. M. van Aerts ◽  
Charles J. Blijdorp ◽  
Niek F. Casteleijn ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Kidney Function ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney

scholarly journals Asymptomatic Pyuria as a Prognostic Biomarker in Autosomal Dominant Polycystic Kidney Disease

Kidney360 ◽  
2021 ◽  
pp. 10.34067/KID.0004292021
Author(s):  
Brian E. Jones ◽  
Yaman G. Mkhaimer ◽  
Laureano J. Rangel ◽  
Maroun Chedid ◽  
Phillip J. Schulte ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Disease Progression ◽  
Polycystic Kidney Disease ◽  
Kidney Function ◽  
Kidney Failure ◽  
Autosomal Dominant ◽  
Prognostic Biomarker ◽  
Kidney Volume ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney

Background: Autosomal dominant polycystic kidney disease (ADPKD) has phenotypic variability only partially explained by established biomarkers that do not readily assess pathologically important factors of inflammation and kidney fibrosis. We evaluated asymptomatic pyuria, a surrogate marker of inflammation, as a biomarker for disease progression. Methods: We performed a retrospective cohort study of adult patients with ADPKD. Patients were divided into asymptomatic pyuria (AP) and no pyuria (NP) groups. We evaluated the effect of pyuria on kidney function and kidney volume. Longitudinal models evaluating kidney function and kidney volume rate of change with respect to incidences of asymptomatic pyuria were created. Results: There were 687 included patients (347 AP, 340 NP). The AP group had more female (65.1% vs 49.4%). Median age at kidney failure was 86 and 80 years in NP and AP groups, respectively (Log-rank, p=0.49) for patients with Mayo Imaging Class (MIC)1A-1B as compared to 59 and 55 years for patients with MIC1C-1D-1E (Log-rank, p=0.02). Compared to NP group, the rate of kidney function (ml/min/1.73m2/year) decline shifted significantly after detection of asymptomatic pyuria in models including all patients (-1.48, p<0.001), MIC 1A-B patients (-1.79 , p<0.001), MIC 1C-1D-1E patients (-1.18, p<0.001), and PKD1 patients (-1.04, p<0.001). Models evaluating kidney volume rate of growth showed no change after incidence of asymptomatic pyuria as compared to NP group. Conclusions: Asymptomatic pyuria is associated with kidney failure and faster kidney function decline irrespective of the ADPKD gene, cystic burden, and cystic growth. These results support asymptomatic pyuria as an enriching prognostic biomarker for the rate of disease progression.-

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