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Chronic Kidney Disease & Mineral Bone Disorder: What are the drivers of disease?
John Cunningham University College London United Kingdom
Mechanisms in chronic kidney disease
Chronic Kidney Disease & Mineral Bone Disorder: What are the - - PowerPoint PPT Presentation
Chronic Kidney Disease & Mineral Bone Disorder: What are the - - PowerPoint PPT Presentation
Mechanisms in chronic kidney disease Chronic Kidney Disease & Mineral Bone Disorder: What are the drivers of disease? John Cunningham University College London United Kingdom Chronic Kidney Disease & Mineral Bone Disorder what are
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Where is the initial “push” as GFR declines? At what are the early adaptive responses aimed?
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Where is the initial “push” as GFR declines? At what are the early adaptive responses aimed?
- difficulty maintaining phosphate excretion
- difficulty making enough calcitriol
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Phosphate: the achilles heel of therapies for CKD
skeletal resist to PTH PTH hyperphosphataemia calcitriol dose Ca x Pi product calcitriol dose
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Relationship Between GFR and TRP in Chronic Renal Disease
J Clin Invest 1968
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Effect of Dietary Phosphate Restriction on PTH
600 400 200 6 12 18 24 PTH ul eq/ml Months CRD CRD-PPR
Rutherford, Slatopolsky et al
6 12 18 2 4 Months Change in osteoclastic resorption surface +2 +4 +6 CRD CRD-PPR
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“Trade-off”
GFR Pi Ca++ PTH GFR Pi Ca++ PTH
Normal diet Pi restriction
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Phosphate is a poor marker for SHPT in early CKD
Martinez I et al. Am J Kidney Dis 1997 mmol/L 5.4 10.8 16.2 21.6
Creatinine clearance (mL/min)
pmol/L iPTH * * * * * *
Creatinine clearance (mL/min)
0.75 1.00 1.25 1.50 Serum ionized calcium Phosphorus 0.50
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Fibroblast Growth Factor-23 in Early Chronic Kidney Disease
Evenepoel et al Clin J Am Soc Nephrol. 2010 5: 1268–1276
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Progression of SHPT: parathyroid hyperplasia
Normal Diffuse Early nodularity Nodular Single nodule Continuous functional demand Gland volume Secretory cells Tominaga Y et al. Curr Opin Nephrol Hypertens 1996 Images courtesy of Dr D Pavlovic Normal Very high PTH VDR CaR
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Impaired calcium sensing in SHPT
from Malberti F et al. Nephrol Dial Transplant 1999 110 100 90 80 70 60 50 40 30 20 10 PTH (%)
Ca++
Normal subject 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Moderate SHPT Severe SHPT Set point 4 4.4 4.8 5.2 5.6 6.0 6.4 mmol/L mg/dL
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Calcimimetic Compounds Increase the Sensitivity of the CaR to Calcium
Cinacalcet binds in the trans- membrane region
- f the CaR
100 80 60 40 20 0.5 1.0 2.0 1.5 PTH Secretion (% of Maximum) Extracellular Ca2+ (mM) Control (1.0 mM) 10 nM (0.60 mM) 100 nM (0.41 mM)
Ca2+ CaR
Nemeth EF, et al. J Pharmacol Exp Ther. 2004
F3C CH3
- HCl
N H
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500 1000 1500 2000 2500 0.6 0.8 1.0 1.2 1.4 1.6 ionized calcium (mmol/L)
*
* * * * * * * * * PTH-Ca curve obtained before and after calcimimetic therapy
n = 10
- p < 0.01
de Francisco, Cunningham et al 2007
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1,25-dihydroxyvitamin D
not only a hormone
D3 (skin) D3 (diet) 25(OH)D2/3 1,25(OH)2D 2/3 periphery
distant targets (hormone) local targets
autocrine/paracrine ‘non classical’ actions
kidney 1,25(OH)2D 2/3 D2 (supplements)
- immune system
- heart
- vasculature
- pancreas
- tumours
- gut
- PT gland
- bone
D3 = cholecalciferol D2 = ergocalciferol
PTH FGF23
Redrawn from Heaney R
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Levin et al KI 2008
1,25(OH)2D3 and 25(OH)D3 deficiency and SHPT SEEK study
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25-hydroxyvitamin D3 suppresses PTH synthesis and secretion by bovine parathyroid cells
Brown A et al Kidney International (2006) 70, 654–659
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Shiizaki et al J Am Soc Nephrol 16: 97-108, 2005
PT Injection with 22-oxacalcitriol
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- 1
2 3 4 5 6 7 8 2.7 7.4 20 55 150 400 1100 3000
- 0.25
- 0.15
- 0.05
0.05 0.15 0.25
log e PTH (pg/ml) Ca
++ (mM)
PTH (pg/ml) baseline 1 month
"Pulse" oral calcitriol - 4 weeks
Cunningham Kidney Int 1999
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Portale et al J Clin Invest 77: 7 1986
Regulation of calcitriol production by phosphate
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Portale et al J Clin Invest 77: 7 1986
Regulation of calcitriol production by phosphate
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Phosphate restriction/supplementation in paediatric CKD
Portale AA et al. J Clin Invest 1984;73:1580–9 Dietary intake of phosphorus
PTH (µLeq/mL) 400 120 100 80 60 40 20 P < 0.05 P < 0.05 Normal Restricted Normal Supplement 80 60 40 20 1,25(OH)2D (pg/mL) P < 0.005 P < 0.01
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All these changes occur long before increases in serum Pi levels are evident
GFR time post Tp <Dialysis>
Modified from Wolf et al J Am Soc Nephrol 2010
Mineral Metabolism in CKD
evolutionary changes pre and post Tp
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after Cunningham 1999, modified Drueke 2011
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Adaptive responses are often more striking than the initial perturbation
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