Erythropoietin and Fibroblast Growth Factor 23 in Autosomal Dominant Polycystic Kidney Disease Patients.
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ABSTRACT:
SUBMITTER: Hanudel MR
PROVIDER: S-EPMC6895647 | biostudies-literature | 2019 Dec
REPOSITORIES: biostudies-literature
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Erythropoietin and Fibroblast Growth Factor 23 in Autosomal Dominant Polycystic Kidney Disease Patients.
Hanudel Mark R MR Salusky Isidro B IB Pereira Renata C RC Wang Wei W You Zhiying Z Nowak Kristen L KL Brosnahan Godela M GM Torres Vicente E VE Chapman Arlene B AB Perrone Ronald D RD Steinman Theodore I TI Bae Kyongtae T KT Gitomer Berenice Y BY Chonchol Michel B MB
Kidney international reports 20190824 12
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Project description:Background and objectivesIncreases in fibroblast growth factor 23 precede kidney function decline in autosomal dominant polycystic kidney disease; however, the role of fibroblast growth factor 23 in autosomal dominant polycystic kidney disease has not been well characterized.Design, setting, participants & measurementsWe measured intact fibroblast growth factor 23 levels in baseline serum samples from 1002 participants in the HALT-PKD Study A (n=540; mean eGFR =91±17 ml/min per 1.73 m2) and B (n=462; mean eGFR =48±12 ml/min per 1.73 m2). We used linear mixed and Cox proportional hazards models to test associations between fibroblast growth factor 23 and eGFR decline, percentage change in height-adjusted total kidney volume, and composite of time to 50% reduction in eGFR, onset of ESRD, or death.ResultsMedian (interquartile range) intact fibroblast growth factor 23 was 44 (33-56) pg/ml in HALT-PKD Study A and 69 (50-93) pg/ml in Study B. In adjusted models, annualized eGFR decline was significantly faster in the upper fibroblast growth factor 23 quartile (Study A: quartile 4, -3.62; 95% confidence interval, -4.12 to -3.12 versus quartile 1, -2.51; 95% confidence interval, -2.71 to -2.30 ml/min per 1.73 m2; P for trend <0.001; Study B: quartile 4, -3.74; 95% confidence interval, -4.14 to -3.34 versus quartile 1, -2.78; 95% confidence interval, -2.92 to -2.63 ml/min per 1.73 m2; P for trend <0.001). In Study A, higher fibroblast growth factor 23 quartiles were associated with greater longitudinal percentage increase in height-adjusted total kidney volume in adjusted models (quartile 4, 6.76; 95% confidence interval, 5.57 to 7.96 versus quartile 1, 6.04; 95% confidence interval, 5.55 to 6.54; P for trend =0.03). In Study B, compared with the lowest quartile, the highest fibroblast growth factor 23 quartile was associated with elevated risk for the composite outcome (hazard ratio, 3.11; 95% confidence interval, 1.84 to 5.25). Addition of fibroblast growth factor 23 to a model of annualized decline in eGFR≥3.0 ml/min per 1.73 m2 did not improve risk prediction.ConclusionsHigher serum fibroblast growth factor 23 concentration was associated with kidney function decline, height-adjusted total kidney volume percentage increase, and death in patients with autosomal dominant polycystic kidney disease. However, fibroblast growth factor 23 did not substantially improve prediction of rapid kidney function decline.
| S-EPMC5586583 | biostudies-literature
Project description:IntroductionAutosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst growth and a loss of functioning renal mass, but a decline in glomerular filtration rate (GFR) and onset of end-stage renal disease (ESRD) occur late in the disease course. There is therefore a great need for early prognostic biomarkers in this disorder.MethodsWe measured baseline serum fibroblast growth factor 23 (FGF23) levels in 192 patients with ADPKD from the Consortium for Radiologic Imaging Studies of PKD (CRISP) cohort that were followed for a median of 13 years and tested the association between FGF23 levels and change over time in height-adjusted total kidney volume (htTKV), GFR, and time to the composite endpoints of ESRD, death, and doubling of serum creatinine.ResultsPatients in the highest quartile for baseline FGF23 level had a higher rate of increase in htTKV (0.95% per year, P = 0.0016), and faster rate of decline in GFR (difference of -1.03 ml/min/1.73 m2 per year, P = 0.005) compared with the lowest quartile, after adjusting for other covariates, including htTKV and genotype. The highest quartile of FGF23 was also associated with a substantial increase in risk for the composite endpoint of ESRD, death, or doubling of serum creatinine (hazard ratio [HR] of 2.45 in the fully adjusted model, P = 0.03).ConclusionFGF23 is a prognostic biomarker for disease progression and clinically important outcomes in ADPKD, and has additive value to established imaging and genetic biomarkers.
| S-EPMC8071629 | biostudies-literature
Project description:Elevated levels of erythropoietin (EPO) are associated with an increased risk of death in renal transplant recipients (RTRs), but the underlying mechanisms remain unclear. Emerging data suggest that EPO stimulates production of the phosphaturic hormone fibroblast growth factor 23 (FGF23), another strong risk factor for death in RTRs. We hypothesized that the hitherto unexplained association between EPO levels and adverse outcomes may be attributable to increased levels of FGF23. We included 579 RTRs (age 51 ± 12 years, 55% males) from the TransplantLines Insulin Resistance and Inflammation Cohort study (NCT03272854). During a follow-up of 7.0 years, 121 RTRs died, of which 62 were due to cardiovascular cause. In multivariable Cox regression analysis, EPO was independently associated with all-cause (HR, 1.66; 95% CI 1.16-2.36; P = 0.005) and cardiovascular death (HR, 1.87; 95% CI 1.14-3.06; P = 0.01). However, the associations were abrogated following adjustment for FGF23 (HR, 1.28; 95% CI 0.87-1.88; P = 0.20, and HR, 1.45; 95% CI 0.84-2.48; P = 0.18, respectively). In subsequent mediation analysis, FGF23 mediated 72% and 50% of the association between EPO and all-cause and cardiovascular death, respectively. Our results underline the strong relationship between EPO and FGF23 physiology, and provide a potential mechanism underlying the relationship between increased EPO levels and adverse outcomes in RTRs.
| S-EPMC7356141 | biostudies-literature
Project description:Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder affecting 1 in 1,000 people and responsible for 10% of cases of the end stage renal disease (ESRD). Apart from renal manifestations, changes in other organs may be present. In the absence of contraindications, patients with ADPKD and ESRD should be referred to renal transplantation. The ADPKD patient may also need liver transplantation, or combined liver and kidney transplantation. Also, the patient with ADPKD may become a potential organ donor. The aim of our paper is to review the problems that the physicians deal with in ADPKD patients in pre- and post-transplant period.
| S-EPMC2843931 | biostudies-literature
Project description:Autosomal dominant polycystic kidney disease (ADPKD) is an inherited multisystem disorder, characterized by renal and extra-renal fluid-filled cyst formation and increased kidney volume that eventually leads to end-stage renal disease. ADPKD is considered the fourth leading cause of end-stage renal disease in the United States and globally. Care of patients with ADPKD was, for a long time, limited to supportive lifestyle measures, due to the lack of therapeutic strategies targeting the main pathways involved in the pathophysiology of ADPKD. As the first FDA approved treatment of ADPKD, Vasopressin (V2) receptor blocking agent, tolvaptan, is an urgently awaited advance for ADPKD patients. In our review, we also shed some lights on what is beyond Tolvaptan as there are other medications in the pipeline and many medications have been or are currently being studied in clinical trials such as Tesevatinib, Metformin and Pravastatin, with the goal of slowing the rate of progression of ADPKD by reducing the increase in total kidney volume or maintaining eGFR. Here, we review updates in the perspectives and management of ADPKD.
| S-EPMC6716585 | biostudies-literature
Project description:Autosomal dominant polycystic kidney disease (ADPKD) is driven by mutations in PKD1 and PKD2 genes. Recent work suggests that epigenetic modulation of gene expression and protein function may play a role in ADPKD pathogenesis. In this study, we identified SMYD2, a SET and MYND domain protein with lysine methyltransferase activity, as a regulator of renal cyst growth. SMYD2 was upregulated in renal epithelial cells and tissues from Pkd1-knockout mice as well as in ADPKD patients. SMYD2 deficiency delayed renal cyst growth in postnatal kidneys from Pkd1 mutant mice. Pkd1 and Smyd2 double-knockout mice lived longer than Pkd1-knockout mice. Targeting SMYD2 with its specific inhibitor, AZ505, delayed cyst growth in both early- and later-stage Pkd1 conditional knockout mouse models. SMYD2 carried out its function via methylation and activation of STAT3 and the p65 subunit of NF-κB, leading to increased cystic renal epithelial cell proliferation and survival. We further identified two positive feedback loops that integrate epigenetic regulation and renal inflammation in cyst development: SMYD2/IL-6/STAT3/SMYD2 and SMYD2/TNF-α/NF-κB/SMYD2. These pathways provide mechanisms by which SMYD2 might be induced by cyst fluid IL-6 and TNF-α in ADPKD kidneys. The SMYD2 transcriptional target gene Ptpn13 also linked SMYD2 to other PKD-associated signaling pathways, including ERK, mTOR, and Akt signaling, via PTPN13-mediated phosphorylation.
| S-EPMC5490754 | biostudies-literature
Project description:BackgroundAutosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disease, is regulated by different forms of cell death, including apoptosis and autophagy. However, the role in ADPKD of ferroptosis, a recently discovered form of cell death mediated by iron and lipid metabolism, remains elusive.MethodsTo determine a pathophysiologic role of ferroptosis in ADPKD, we investigated whether the absence of Pkd1 (encoding polycystin-1) affected the expression of key factors involved in the process of ferroptosis, using Western blot and qRT-PCR analysis in Pkd1 mutant renal cells and tissues. We also examined whether treatment with erastin, a ferroptosis inducer, and ferrostain-1, a ferroptosis inhibitor, affected cyst growth in Pkd1 mutant mouse models.ResultsWe found that kidney cells and tissues lacking Pkd1 exhibit extensive metabolic abnormalities, including reduced expression of the system Xc- amino acid antiporter (critical for import of cystine), of iron exporter (ferroportin), and of GPX4 (a key and negative regulator of ferroptosis). The abnormalities also include increased expression of iron importers (TfR1, DMT1) and HO-1, which in turn result in high iron levels, low GSH and GPX4 activity, increased lipid peroxidation, and propensity to ferroptosis. We further found that erastin increased, and ferrostatin-1 inhibited ferroptotic cell death and proliferation of Pkd1-deficient cells in kidneys from Pkd1 mutant mice. A lipid peroxidation product increased in Pkd1-deficient cells, 4HNE, promoted the proliferation of survived Pkd1 mutant cells via activation of Akt, S6, Stat3, and Rb during the ferroptotic process, contributing to cyst growth.ConclusionThese findings indicate that ferroptosis contributes to ADPKD progression and management of ferroptosis may be a novel strategy for ADPKD treatment.
| S-EPMC8806097 | biostudies-literature
Project description:Autosomal dominant polycystic kidney disease (ADPKD) involves the development and persistent growth of fluid filled kidney cysts. In a recent study, we showed that ADPKD kidney cyst epithelial cells can stimulate the proliferation and differentiation of peri-cystic myofibroblasts. Although dense myofibroblast populations are often found surrounding kidney cysts, their role in cyst enlargement or fibrosis in ADPKD is unclear. To clarify this, we examined the effect of myofibroblast depletion in the Pkd1RC/RC (RC/RC) mouse model of ADPKD. RC/RC;αSMAtk mice that use the ganciclovir-thymidine kinase system to selectively deplete α-smooth muscle actin expressing myofibroblasts were generated. Ganciclovir treatment for four weeks depleted myofibroblasts, reduced kidney fibrosis and preserved kidney function in these mice. Importantly, myofibroblast depletion significantly reduced cyst growth and cyst epithelial cell proliferation in RC/RC;αSMAtk mouse kidneys. Similar ganciclovir treatment did not alter cyst growth or fibrosis in wild-type or RC/RC littermates. In vitro, co-culture with myofibroblasts from the kidneys of patients with ADPKD increased 3D microcyst growth of human ADPKD cyst epithelial cells. Treatment with conditioned culture media from ADPKD kidney myofibroblasts increased microcyst growth and cell proliferation of ADPKD cyst epithelial cells. Further examination of ADPKD myofibroblast conditioned media showed high levels of protease inhibitors including PAI1, TIMP1 and 2, NGAL and TFPI-2, and treatment with recombinant PAI1 and TIMP1 increased ADPKD cyst epithelial cell proliferation in vitro. Thus, our findings show that myofibroblasts directly promote cyst epithelial cell proliferation, cyst growth and fibrosis in ADPKD kidneys, and their targeting could be a novel therapeutic strategy to treat PKD.
| S-EPMC9822873 | biostudies-literature
Project description:Background and objectivesTo evaluate the growth pattern of kidney cyst number and cyst volume in association with kidney size, demographics, and genotypes in autosomal dominant polycystic kidney disease.Design, setting, participants, & measurementsKidney cyst number and cyst volume were measured from serial magnetic resonance images, giving a maximum follow-up of 14.23 years, from 241 patients with autosomal dominant polycystic kidney disease (15-46 years old at baseline). The growth pattern was analyzed, in association with sex, age, height-adjusted total kidney volume, and genotype, using linear mixed models of repeated measurements and tests of interactions with age (as a time-dependent covariate) to assess rates of change over time. Models were also fit using Irazabal class. Genotypic groups were characterized as either (1) PKD1 truncating, PKD1 nontruncating, and PKD2 plus patients with no mutation detected; or (2) in combination with PKD1 mutation strength groups.ResultsImaging and genetic data were collected (at least one visit) for 236 participants. The mean height-adjusted total cyst number increased exponentially over time from a baseline value of 762 to 1715 at the last clinic visit, while the mean height-adjusted total cyst volume increased exponentially from 305 to 770 ml. Height-adjusted total kidney volume, height-adjusted total cyst number, and height-adjusted total cyst volume were all highly correlated over time. Female participants and participants with larger height-adjusted total kidney volume at baseline showed smaller rates of change in the log of height-adjusted total cyst number and cyst volume. PKD1 was associated with significant increases in both cyst number and volume at a given age, but genotype did not significantly affect the rate of growth.ConclusionsBoth height-adjusted total cyst number and height-adjusted total cyst volume increased exponentially and more than doubled over 14.23 years of follow-up. Compared with PKD2 plus no mutation detected, PKD1 was associated with a greater cyst number and volume at a given age, but no significant difference in the rate of growth.
| S-EPMC6556721 | biostudies-literature
Project description: Not available
| S-EPMC7005356 | biostudies-literature