The effect of nephrectomy on Klotho, FGF-23 and bone metabolism

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Abstract

Background

Increased concentration of fibroblast growth factor 23 (FGF-23) and decreased levels of soluble Klotho (sKL) are linked to negative clinical outcomes among patients with chronic kidney disease and acute kidney injury. Therefore, it is reasonable to hypothesize that GFR reduction caused by nephrectomy might alter mineral metabolism and induces adverse consequences. Whether nephrectomy due to urological indications causes derangements in FGF-23 and sKL has not been studied. The aim of the study was to evaluate the effect of acute GFR decline due to unilateral nephrectomy on bone metabolism, FGF-23 and sKL levels.

Methods

This is a prospective, single-centre observational study of patients undergoing nephrectomy due to urological indications. Levels of C-terminal FGF-23 (c-FGF-23), sKL and bone turnover markers [β-crosslaps (CTX), bone-specific alkaline phosphatase (bALP) and tartrate-resistant acid phosphatase 5b (TRAP 5b)] were measured before and after surgery (5 ± 2 days).

Results

Twenty-nine patients were studied (14 females, age 63.0 ± 11.6, eGFR 87.3 ± 19.2 ml/min/1.73 m ²). After surgery, eGFR significantly declined ( p < 0.0001). Nephrectomy significantly decreased sKL level [709.8 (599.9–831.2) vs. 583.0 (411.7–752.6) pg/ml, p < 0.001] and did not change c-FGF-23 concentration [70.5 (49.8–103.3) vs. 77.1 (60.5–109.1) RU/ml, p = 0.9]. Simultaneously, alterations in bone turnover markers were observed. Serum concentration of CTX increased [0.49 (0.4–0.64) vs. 0.59 (0.46–0.85) ng/ml, p = 0.001], while bALP and TRAP 5b decreased [23.6 (18.8–31.4) vs. 17.9 (15.0–22.0) U/l, p < 0.0001 and 3.3 (3.0–3.7) vs. 2.8 (2.3–3.2) U/l, p < 0.001, respectively].

Conclusions

Nephrectomy among patients with preserved renal function before surgery does not increase c-FGF-23 but reduces sKL. Moreover, nephrectomy results in derangements in bone turnover markers in short-term follow-up. These changes may participate in pathogenesis of bone disease after nephrectomy.

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Most cited references 35

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Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease.

Tamara Isakova, Huiliang Xie, Wei Yang … (2011)

A high level of the phosphate-regulating hormone fibroblast growth factor 23 (FGF-23) is associated with mortality in patients with end-stage renal disease, but little is known about its relationship with adverse outcomes in the much larger population of patients with earlier stages of chronic kidney disease. To evaluate FGF-23 as a risk factor for adverse outcomes in patients with chronic kidney disease. A prospective study of 3879 participants with chronic kidney disease stages 2 through 4 who enrolled in the Chronic Renal Insufficiency Cohort between June 2003 and September 2008. All-cause mortality and end-stage renal disease. At study enrollment, the mean (SD) estimated glomerular filtration rate (GFR) was 42.8 (13.5) mL/min/1.73 m(2), and the median FGF-23 level was 145.5 RU/mL (interquartile range [IQR], 96-239 reference unit [RU]/mL). During a median follow-up of 3.5 years (IQR, 2.5-4.4 years), 266 participants died (20.3/1000 person-years) and 410 reached end-stage renal disease (33.0/1000 person-years). In adjusted analyses, higher levels of FGF-23 were independently associated with a greater risk of death (hazard ratio [HR], per SD of natural log-transformed FGF-23, 1.5; 95% confidence interval [CI], 1.3-1.7). Mortality risk increased by quartile of FGF-23: the HR was 1.3 (95% CI, 0.8-2.2) for the second quartile, 2.0 (95% CI, 1.2-3.3) for the third quartile, and 3.0 (95% CI, 1.8-5.1) for the fourth quartile. Elevated fibroblast growth factor 23 was independently associated with significantly higher risk of end-stage renal disease among participants with an estimated GFR between 30 and 44 mL/min/1.73 m(2) (HR, 1.3 per SD of FGF-23 natural log-transformed FGF-23; 95% CI, 1.04-1.6) and 45 mL/min/1.73 m(2) or higher (HR, 1.7; 95% CI, 1.1-2.4), but not less than 30 mL/min/1.73 m(2). Elevated FGF-23 is an independent risk factor for end-stage renal disease in patients with relatively preserved kidney function and for mortality across the spectrum of chronic kidney disease.

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Fibroblast growth factor-23 and cardiovascular events in CKD.

Xiaoming Zhang, Akinlolu Ojo, Wei Yang … (2014)

An elevated level of fibroblast growth factor-23 (FGF-23) is the earliest abnormality of mineral metabolism in CKD. High FGF-23 levels promote left ventricular hypertrophy but not coronary artery calcification. We used survival analysis to determine whether elevated FGF-23 is associated with greater risk of adjudicated congestive heart failure (CHF) and atherosclerotic events (myocardial infarction, stroke, and peripheral vascular disease) in a prospective cohort of 3860 participants with CKD stages 2-4 (baseline estimated GFR [eGFR], 44±15 ml/min per 1.73 m(2)). During a median follow-up of 3.7 years, 360 participants were hospitalized for CHF (27 events/1000 person-years) and 287 had an atherosclerotic event (22 events/1000 person-years). After adjustment for demographic characteristics, kidney function, traditional cardiovascular risk factors, and medications, higher FGF-23 was independently associated with graded risk of CHF (hazard ratio [HR], 1.45 per doubling [95% confidence interval (CI), 1.28 to 1.65]; HR for highest versus lowest quartile, 2.98 [95% CI, 1.97 to 4.52]) and atherosclerotic events (HR per doubling, 1.24 [95% CI, 1.09 to 1.40]; HR for highest versus lowest quartile, 1.76 [95% CI, 1.20 to 2.59]). Elevated FGF-23 was associated more strongly with CHF than with atherosclerotic events (P=0.02), and uniformly was associated with greater risk of CHF events across subgroups stratified by eGFR, proteinuria, prior heart disease, diabetes, BP control, anemia, sodium intake, income, fat-free mass, left ventricular mass index, and ejection fraction. Thus, higher FGF-23 is independently associated with greater risk of cardiovascular events, particularly CHF, in patients with CKD stages 2-4.

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The beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel.

Q Chang, S Hoefs, A W van der Kemp … (2005)

Blood calcium concentration is maintained within a narrow range despite large variations in dietary input and body demand. The Transient Receptor Potential ion channel TRPV5 has been implicated in this process. We report here that TRPV5 is stimulated by the mammalian hormone klotho. Klotho, a beta-glucuronidase, hydrolyzes extracellular sugar residues on TRPV5, entrapping the channel in the plasma membrane. This maintains durable calcium channel activity and membrane calcium permeability in kidney. Thus, klotho activates a cell surface channel by hydrolysis of its extracellular N-linked oligosaccharides.

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Author and article information

Contributors

Katarzyna Kakareko: +48 85 740 94 58 , kponikwicka@o2.pl

Journal

Journal ID (nlm-ta): Int Urol Nephrol

Journal ID (iso-abbrev): Int Urol Nephrol

Title: International Urology and Nephrology

Publisher: Springer Netherlands (Dordrecht )

ISSN (Print): 0301-1623

ISSN (Electronic): 1573-2584

Publication date (Electronic): 27 January 2017

Publication date PMC-release: 27 January 2017

Publication date (Print): 2017

Volume: 49

Issue: 4

Pages: 681-688

Affiliations

[1 ]ISNI 0000000122482838, GRID grid.48324.39, I Department of Nephrology and Transplantation with Dialysis Unit, , Medical University of Bialystok, ; Ul. Zurawia 14, 15-540 Białystok, Poland

[2 ]ISNI 0000000122482838, GRID grid.48324.39, II Department of Nephrology and Hypertension with Dialysis Unit, , Medical University of Bialystok, ; Białystok, Poland

[3 ]Department of Oncological and General Urology, J. Sniadecki Provincial Hospital, Białystok, Poland

Article

Publisher ID: 1519

DOI: 10.1007/s11255-017-1519-9

PMC ID: 5357491

PubMed ID: 28130714

SO-VID: 89a47bee-1f56-4533-9ed5-2764693c1ed5

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 19 July 2016

Date accepted : 17 January 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100005297, Uniwersytet Medyczny w Bialymstoku;

Award ID: N/ST/ZB/16/001/1154 and N/ST/ZB/16/002/1154

Award Recipient : Tomasz Hryszko

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ScienceOpen disciplines: Nephrology

Keywords: acute gfr decline,nephrectomy,klotho,fgf-23,bone metabolism

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ScienceOpen disciplines: Nephrology

Keywords: acute gfr decline, nephrectomy, klotho, fgf-23, bone metabolism

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The effect of nephrectomy on Klotho, FGF-23 and bone metabolism

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Karger: Nephrology

Most cited references 35

Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease.

Fibroblast growth factor-23 and cardiovascular events in CKD.

The beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel.

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