AltesundNeuesbeider CKD-MBD
Transcript of AltesundNeuesbeider CKD-MBD
Altes und Neues bei der CKD-MBD(Eberhard-Ritz-Lecture)
Tilman B. DrüekeInserm Unit 1018, CESP, Team 5Paul Brousse hospitalVillejuif/Paris, France
Potential conflicts of interest
•SpeakerAkebia; Amgen; Astellas; Chugai; Kyowa Hakko Kirin; Sanofi-Genzyme
•ConsultingAmgen; F. Hoffman-La Roche; FMC; Glaxo-Smith-Kline; KfH-Stiftung Präventivmedizin; Vifor
My relation with Eberhardt Ritz
•Always learning from him !
•Common reports(Pubmed): 8
•Common book
chapters: near 10?
My relation with Eberhardt Ritz
•Always listening to others !
•Common reports(Pubmed): 8
•Common book
chapters: near 10?
CKD-MBD – The Past
1804–1892 Specimen L333.1, Hunterian Museum, Royal College of Surgeons, London
1852: Discovery of parathyroid gland by Sir Richard Owenin Indian rhinoceros
Eknoyan G. Am J Kidney Dis 1995;26:801–7.
Malluche H, Ritz E et al, KI 1976; 9: 355-362
Progressive increase of woven osteoid(reflecting 2°hyperpara) with decreasing GFR
Amann K, Ritz E et al, JASN 1994; 4: 1814-1819
Stimulation of cardiac fibrosis in uremic rats with secondary hyperparathyroidism
(Reichel et al, NDT1991; 6: 1 62-9)
GFR (ml/min)Normal 40-60 20-4060-90
60
50
40
30
20
10
70
80
1,25 (OH)2D3 (n/gl)
Progressive reduction of serum 1,25 diOH vitD in CKD
1,25 diOH vit D production and VDR expressionin human monocytes in vitro
VDR mRNA expression in vitro: human monocytes versus
human macrophages
1,25 diOH vit D production in vitroin human monocytes and
monocyte derived macrophages
Kreutz ... Ritz & Reichel, Blood 1993;82:1300-7
CKD-MBD – Definition Issue
•Abnormal bone and mineral metabolism in CRF
•2°hyperparathyroidism
•Renal osteodystrophy
•Mixed bone disease
CKD-MBD – More recent Past
Moe S et al, KI 2006;69:1945-53
CKD-MBD – The more recent Past
Mutation of klotho gene in the mouse
• reduced life expectancy
• decrease of spontaneous activity
• infertility
• skin thinning and atrophy
Mean survival
Control : 600 days
Klotho -/- : 380 days
Kuro-o M et al, Nature 1997;390:45-51
• high serum phosphorus, calcitriol
• soft tissue calcifications
• osteopenia (low bone turnover)
• atherosclerosis/arteriosclerosis
Vascular phenotypes in klotho mice resembling CKD
Aorta calcification
Arteriolosclerosis (kidney)Atherosclerosis (muscle)
Kuro-o M et al, Nature 1997;390:45-51
Stubbs JR et al, JASN 2007;18:2116-24
FGF23-/- mice : similar phenotype as kl-/- miceAorta calcification in FGF23-/- vs wild-type mice on regular diet
A, Alizarin Red-S stainC, von Kossa stain
Komaba and Fukagawa. Kidney Int 2010;77:292–298 (slightly modified)
Disturbed interactions between FGF23, klotho,calcium, phosphate, calcitriol, and PTH in CKD
Hypocalcemia
=
Gutierrez OM et al,NEJM 2008; 359: 584-92
High FGF23 and mortality in HD patients:independent association (Serum FGF23 quartiles)
Faul C et al, JCI 2011;121:4393-408
Left ventricular hypertrophyafter intracardial FGF23 injection in mice
Mechanisms of FGF23-induced signal transduction
Vervloet M, Nat Rev Nephrol 2019;15:109-20
FGF23 – key FGF receptor (FGFR) signaling pathways
Vervloet M, Nat Rev Nephrol 2019;15:109-20
Hu MC et al, JASN 2015;26:1290-1302
Left ventricular hypertrophy and cardiac fibrosisin Klotho deficient (kl/kl) mice
Hu MC et al, JASN 2015;26:1290-1302
Left ventricular hypertrophy and cardiac fibrosisin uninephrectomized (UNX) mice
Time profile of serum biomarkers in the course of CKD-MBD –Schematic view
Drüeke & Massy, Kidney Int 2016;89:289-302
Time profile of serum biomarkers in the course of CKD-MBD –Schematic view
Drüeke & Massy, Kidney Int 2016;89:289-302
CKD-MBD – Present
•PTH: gut microbiota and bone effect•PTH oxidation
•FGF23 and the heart
•FGF23: inflammation, hypoxia and iron metabolism
Drueke & Massy, KI 2020; 98: 269-72
PTH and bone formation vs resorption: role of gut microbiota
Ursem SR et al, KI 2021 (in press)
Highly significant correlation between serum total PTHand non-oxidized PTH in ESKD patients
Ursem SR et al, KI 2021 (in press)
Comparable distinction of bone turnover patterns by total PTH and non-oxidized PTH in ESKD patients
CKD-MBD – Present
•PTH: gut microbiota and bone effect; PTH oxidation
•FGF23 and the heart
•FGF23: inflammation, hypoxia and iron metabolism
Pastor-Arroyo EM et al,KI 2018;94:49-59
No cardiac hypertrophy in novel mouse model of XLH (HEM)despite very high FGF23 levels
Faul C et al, KI 2018;94:7-11
Effects of FGF23 on kidney and heart dependon source and condition of FGF23 elevation
XLH, X-linked hypophosphatemiaARHR, Autosomal recessive hypophosphatemic rickets
CKD-MBD – Present
•PTH: gut microbiota and bone effect; PTH oxidation
•FGF23 and the heart
•FGF23: inflammation, hypoxia and iron metabolism
FGF23 and inflammation –a vicious cycle
Vervloet M,Nat Rev Nephrol 2019;15:109-20
FGF23 stimulates CRP and IL-6 productionin mouse hepatocytes in vitro
Singh S et al, KI 2016;90:985-96
TNF increases plasma and bone FGF23,and TNF Ab reduced plasma FGF23
Egli-Spichtig D et al, Kidney Int 2019;96:890-905
WT mice after TNF (vsvehicle) administration
Osteocyte exposureto 1,25D and TNF (FGF23 mRNA)
Mice with oxalate nephropathyafter TNF neutralization
FGF23: cross-talk with iron metabolism and inflammation in CKD
Babitt JL & Sitara D, Curr Opin Nephr Hptn 2019;28:304-10
Reversal of CKD associated iron deficiency and anemiaby blocking FGF23 action in 5/6 Nx mice
Agoro F et al, FASEB J 2018;32:3752-64
FGF23measurement/
targeting:clinicallyuseful?
Therapeutic response monitoring
DiagnosisEarly biochemical detection in CKD-MBD;
iFGF23 / cFGF23 ratio
Therapy selectionPi binders; calcimimetics;vitamin D; Fe; KTx; Ab?
Risk stratificationCVD; anemia;inflammation
Derived from Smith ER, CJASN 2014;9:1283-1303
Effect of cinacalcet on serum FG23 levels and outcomes in HD patients – EVOLVE post-hoc analysis (medians [Q1, Q3])
Moe SM et al, Circulation 2015;132:27-39
Shalhoub V et al, JCI 2012;122:2543-53
Complete FGF23 neutralization by FGF23-Ab in uremic rats: higher mortality risk
Improvement in XLH rickets severity by FGF23 blockade with monoclonal antibody burosumab
Imel EA et al, Lancet 2019;393:2416-27
Conclusion
1. Increasingly complex interaction of factors involved in CKD-MBD
2. Sec. hyperparathyroidism much better controlled at present than 30-50 years ago; risk of excessive control
3. Persistent uncertainty as to the usefulness of measuring serum FGF23 and of controlling FGF23 and a-klotho levels
4. Open issue: does an optimal control of factors playing a role in CKD-MBD prevent fractures, other morbidities, and global mortality?