Soluble klotho and autosomal dominant polycystic kidney disease.
+8 authors
Journal: 2012/June - Clinical Journal of the American Society of Nephrology
ISSN: 1555-905X
Abstract:
OBJECTIVE
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.
METHODS
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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Clin J Am Soc Nephrol 7(2): 248-257
PMID: 22193235

Soluble Klotho and Autosomal Dominant Polycystic Kidney Disease

+4 authors
Institute of Physiology and Zurich Center for Integrative Human Physiology, Zurich, Switzerland;
Division of Nephrology,
Institute of Clinical Chemistry,
Institute for Diagnostic Radiology, and
Division of Endocrinology, University Hospital, Zurich, Switzerland; and
Center for Nephrology, Royal Free Hospital and University College of London, London, United Kingdom
Correspondence: Dr. Andreas L. Serra, Division of Nephrology, University Hospital, Rämistrasse 100, 8091 Zurich, Switzerland. Email: hc.zsu@arres.saerdna
Received 2011 Sep 2; Accepted 2011 Nov 4.
Copyright © 2012 by the American Society of Nephrology

Summary

Background 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; CKD stage 2, 60–89 ml/min per 1.73 m).

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.

Summary

Values expressed with a plus/minus sign are the mean ± SD. ADPKD1-2, autosomal dominant polycystic kidney disease with CKD stage 1 and 2; CKD1-2, CKD stage 1 and 2 without polycystic kidney disease; XLH, X-linked hypophosphatemia; eGFR, estimated GFR.

Values expressed with a plus/minus sign are the least-square mean ± SD. ADPKD1-2, autosomal dominant polycystic kidney disease with CKD stage 1 and 2; CKD1-2, CKD stage 1 and 2 without polycystic kidney disease; XLH, X-linked hypophosphatemia; CI, confidence interval; FGF23, fibroblast growth factor 23; TmP/GFR, ratio of the maximum rate of tubular phosphate reabsorption to the GFR.

Values expressed with a plus/minus sign are the least-square mean. TMP/GFR, ratio of the maximum rate of tubular phosphate reabsorption to the GFR; ADPKD1-2, autosomal dominant polycystic kidney disease with CKD stage 1 and 2; CKD1-2, CKD stage 1 and 2 without polycystic kidney disease; XLH, X-linked hypophosphatemia; CI, confidence interval; FGF23, fibroblast growth factor 23.

Acknowledgments

The authors thank Julia Hofmann, Ruth Russi, and Marian Struker for excellent technical assistance; Cornelia Zwimpfer for performing FGF23 assays in sera from XLH patients; and especially Marieluise Wipperman at TecoMedical Group for support with the Klotho test assays.

Funding was provided by the Swiss National Science Foundation (3100030_132597/1) to A.S. and the Center for Integrative Human Physiology at the University of Zurich to A.S. and C.W.

Acknowledgments

Footnotes

Published online ahead of print. Publication date available at www.cjasn.org.

Footnotes

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