Patients with autosomal dominant polycystic kidney disease have elevated fibroblast growth factor 23 levels and a renal leak of phosphate

Pavik, Ivana; Jaeger, Philippe; Kistler, Andreas D.; Poster, Diane; Krauer, Fabienne; Cavelti-Weder, Claudia; Rentsch, Katharina; Wüthrich, Rudolf P.; Serra, Andreas L.

doi:10.1038/ki.2010.375

Cited by 78 publications

(66 citation statements)

References 36 publications

(39 reference statements)

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“…In contrast, elevated FGF23 levels in patients with CKD may play an essential role in maintaining normal serum phosphate levels at CKD stages 1 and 2 (15)(16)(17). Recently we reported that serum levels of FGF23 are markedly elevated in patients with ADPKD (18). As has been seen with tumor-induced osteomalacia, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and XLH, this occurred even in the presence of a normal GFR.…”

Section: Introductionmentioning

confidence: 79%

Soluble Klotho and Autosomal Dominant Polycystic Kidney Disease

Pavik

Jaeger

Ebner

et al. 2012

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Fibroblast growth factor 23 (FGF23) levels are elevated in patients with autosomal dominant polycystic kidney disease (ADPKD) and X-linked hypophosphatemia (XLH), but only the latter is characterized by a renal phosphate wasting phenotype. This study explored potential mechanisms underlying resistance to FGF23 in ADPKD.Design, setting, participants, & measurements FGF23 and Klotho levels were measured, and renal phosphate transport was evaluated by calculating the ratio of the maximum rate of tubular phosphate reabsorption to GFR (TmP/GFR) in 99 ADPKD patients, 32 CKD patients, 12 XLH patients, and 20 healthy volunteers. ADPKD and CKD patients were classified by estimated GFR (CKD stage 1, $90 ml/min per 1.73 m 2 ; CKD stage 2, 60-89 ml/min per 1.73 m 2 ).Results ADPKD patients had 50% higher FGF23 levels than did XLH patients; TmP/GFR was near normal in most ADPKD patients and very low in XLH patients. Serum Klotho levels were lowest in the ADPKD group, whereas the CKD and XLH groups and volunteers had similar levels. ADPKD patients with an apparent renal phosphate leak had two-fold higher Klotho levels than those without. Serum Klotho values correlated inversely with cyst volume and kidney growth.Conclusions Loss of Klotho might be a consequence of cyst growth and constrain the phosphaturic effect of FGF23 in most patients with ADPKD. Normal serum Klotho levels were associated with normal FGF23 biologic activity in all XLH patients and a minority of ADPKD patients. Loss of Klotho and FGF23 increase appear to exceed and precede the changes that can be explained by loss of GFR in patients with ADPKD.

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Section: Introductionmentioning

confidence: 79%

Soluble Klotho and Autosomal Dominant Polycystic Kidney Disease

Pavik

Jaeger

Ebner

et al. 2012

Clinical Journal of the American Society of Nephrology

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“…1D, E) with the induction of FGF23 occurring prior to the elevation of serum PTH as observed in human studies. (55,56) Disruption in the Data expressed as mean AE SEM from histomorphometric analysis of isolated from animals at 6, 9, 12, or 15 weeks of age.…”

Section: Discussionmentioning

confidence: 99%

Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

Sabbagh

Graciolli

O’Brien

et al. 2012

Journal of Bone and Mineral Research

232

219

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Chronic kidney disease–mineral bone disorder (CKD‐MBD) is defined by abnormalities in mineral and hormone metabolism, bone histomorphometric changes, and/or the presence of soft‐tissue calcification. Emerging evidence suggests that features of CKD‐MBD may occur early in disease progression and are associated with changes in osteocyte function. To identify early changes in bone, we utilized the jck mouse, a genetic model of polycystic kidney disease that exhibits progressive renal disease. At 6 weeks of age, jck mice have normal renal function and no evidence of bone disease but exhibit continual decline in renal function and death by 20 weeks of age, when approximately 40% to 60% of them have vascular calcification. Temporal changes in serum parameters were identified in jck relative to wild‐type mice from 6 through 18 weeks of age and were subsequently shown to largely mirror serum changes commonly associated with clinical CKD‐MBD. Bone histomorphometry revealed progressive changes associated with increased osteoclast activity and elevated bone formation relative to wild‐type mice. To capture the early molecular and cellular events in the progression of CKD‐MBD we examined cell‐specific pathways associated with bone remodeling at the protein and/or gene expression level. Importantly, a steady increase in the number of cells expressing phosphor‐Ser33/37‐β‐catenin was observed both in mouse and human bones. Overall repression of Wnt/β‐catenin signaling within osteocytes occurred in conjunction with increased expression of Wnt antagonists (SOST and sFRP4) and genes associated with osteoclast activity, including receptor activator of NF‐κB ligand (RANKL). The resulting increase in the RANKL/osteoprotegerin (OPG) ratio correlated with increased osteoclast activity. In late‐stage disease, an apparent repression of genes associated with osteoblast function was observed. These data confirm that jck mice develop progressive biochemical changes in CKD‐MBD and suggest that repression of the Wnt/β‐catenin pathway is involved in the pathogenesis of renal osteodystrophy. © 2012 American Society for Bone and Mineral Research.

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“…Several other serum and laboratory factors have been associated with various aspects of ADPKD severity, including serum uric acid, HDL, fibroblast growth factor-23, collagenderived peptides, NGAL, IL-8, and TNFa. 78,[86][87][88][91][92][93][94] Although some of these factors may contribute to ADPKD progression, confirmation in additional studies is required as well as biomarker validation. …”

Section: Serum Copeptin Levelsmentioning

confidence: 99%

Predictors of Autosomal Dominant Polycystic Kidney Disease Progression

Schrier

Brosnahan

Cadnapaphornchai

et al. 2014

Journal of the American Society of Nephrology

140

105

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Autosomal dominant polycystic kidney disease is a genetic disorder associated with substantial variability in its natural course within and between affected families. Understanding predictors for rapid progression of this disease has become increasingly important with the emergence of potential new treatments. This systematic review of the literature since 1988 evaluates factors that may predict and/or effect autosomal dominant polycystic kidney disease progression. Predicting factors associated with early adverse structural and/or functional outcomes are considered. These factors include PKD1 mutation (particularly truncating mutation), men, early onset of hypertension, early and frequent gross hematuria, and among women, three or more pregnancies. Increases in total kidney volume and decreases in GFR and renal blood flow greater than expected for a given age also signify rapid disease progression. Concerning laboratory markers include overt proteinuria, macroalbuminuria, and perhaps, elevated serum copeptin levels in affected adults. These factors and others may help to identify patients with autosomal dominant polycystic kidney disease who are most likely to benefit from early intervention with novel treatments.

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Patients with autosomal dominant polycystic kidney disease have elevated fibroblast growth factor 23 levels and a renal leak of phosphate

Cited by 78 publications

References 36 publications

Soluble Klotho and Autosomal Dominant Polycystic Kidney Disease

Soluble Klotho and Autosomal Dominant Polycystic Kidney Disease

Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

Predictors of Autosomal Dominant Polycystic Kidney Disease Progression

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