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

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



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 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?

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