CKD-MBD

05/2015 Dallas Area Dietitians

Jorge Roman-Latorre MDDNA

Following reflects only my personal opinion today

It does not represents DNA or Fresenius

Considers current guidelines

Does not necessarily follow any one protocol

Complex subject : changing fast

We do not have all answers!!!

CKD Ca PO4 PTH

1937 Donahue : CKD Rats had increased Calcium in kidney tissue, proportional to parathyroid weight. Parathyroidectomy prevented Ca deposition in Kidneys

1978 Ibels : Rats subtotal Nephrectomy on either low Phosphorus diet or regular chow + Al(OH)3 : Less uremia , Normal K ; controls had interstitial nephritis, not controlled for protein intake

Man made disease

not noticeable without dialysis

2011 > 2.2M dialysis + .6 M grafted

Rare before chronic dialysis ( 1960 Seattle )

Focus has changed last 35-40 years

From Renal Rickets to a silent common disorder often fatal

Foley RN, et al. Am J Kidney Dis. 1998;32:S112-

S119.

GP: General

Population.

0.001

0.01

0.1

1

10

100

25-34 35-44 45-54 55-64 66-74 75-84 >85

GP Male

GP Female

GP Black

GP White

Dialysis Male

Dialysis Female

Dialysis Black

Dialysis White

Age (years)

An

nu

al

CV

D M

ort

ali

ty (

%)

Definition of CKD-Mineral and Bone Disorder

A systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following:

Abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism

Abnormalities in bone turnover, mineralization, volume, linear growth, or strength

Vascular or other soft tissue calcification

Moe S, et al. Kidney Int 69: 1945, 2006

Excess Mortality (previous slide)

excess Fractures 20% excess Block G.A. CJASN 8:2132-2140 2013

More Kidney Damage = CKD Progression

Renal Osteodystrophy ( a very mixed bag)

Stiff Vessels; Media Calcification; abnormal pulse wave velocity , abnormal medial thickness

Coronary scores :Calcified heart valves

Excess Atrial Arrythmias?

Lungs, soft tissue calcification; pruritus

Sexual Dysfunction

CVA’s?

Pathophysiology of CKD-MBD

PO4

Skeletal

Resistance to

PTH

GFR

PTHCa2

FGF-23

Disturbed

mineralization

Calcitriol

MEPE

(Matrix extracellular

phospho-glycoprotein

Hyperparathyroid

bone

CKD-MBD Where can we act? Nutritional Vit D (Calcidiol level 50-100)

PO4 poisoning: Limit inorganic intake

binders

Proton Poisoning (acidosis)

Ca++ not needed !!

PTH Phosphaturic toxin

FGF 23

My Pill will fix it!!!

Vit Ds and VDRA’s Steroid Hormones (Seco Steroids)

Not true vitamins : skin can make it (naked in sun)

Receptors in multiple cells and tissues

All Vit D’s can activate receptor at different doses

Activation in Steps Liver 25-OH

Kidneys and multiple tissues 1-OH

1,25-OH Endocrine, Paracrine, Autocrine effects

1,25-OH circulating levels = little meaning

Physiology different from Pharmacological !!

Zehnder D J (2001 ) Clin Endocrinol Metab. Feb;86(2):888-94

• skin (basal keratinocytes

• hair follicles)

• lymph nodes (granulomata)

• colon (epithelial cells and parasympathetic ganglia)

• pancreas (islets)

• adrenal medulla

• brain (cerebellum and cerebral cortex),

• placenta (decidual and trophoblastic cells).

Extrarenal distribution of 1 alpha-hydroxylase

Vit D Receptors :Vitamin D receptor (VDR) is a member of the nuclear

receptor superfamily of ligand-activated transcription factors

RARs (retinoic acid receptors)

TRs (thyroid hormone receptors)

GRs (glucocorticoid receptors)

ERs and PRs (estrogen and progesterone receptors)

PPARs (peroxisome proliferator-activated receptors)

*RXRs (retinoid X receptors)

McDonnell DP, Science. 235:1214-1217, 1987.Baker, et al. Proc Natl Acad Sci U S A. 85 (10): 3294–3298, 1988.

System Tissue

Gastrointestinal Esophagus, stomach, small intestine, large intestine, colon

Arterial Vessels Vascular smooth muscle cells

Hepatic Liver parenchyma cells

Renal Proximal and distal tubules, collecting duct

Endocrine Parathyroid, pancreatic b-cells, thyroid C-cells

Exocrine Parotid gland, sebaceous gland

Reproductive Testis, ovary, placenta, uterus, endometrium, yolk sac,

Immune Thymus, bone marrow, B cells, T cells

Respiratory Lung alveolar cells

Musculoskeletal Osteoblasts, osteocytes, chondrocytes, striated muscle

Epidermis/appendage Skin, breast, hair follicles

Central nervous system Brain neurons

Connective tissue Fibroblasts, stroma

Vitamin D Receptor Distribution

Action of Vitamin DClassical Actions

Calcium / Phosphorus

Homeostasis

Non-Classical Actions

Regulation of cell proliferation

and differentiation

Regulation of immune function

Endocrine effects Insulin resistance

Inflammation

Modulation of the renin-

angiotension system

Hypertension

Renal Function

Muscle functionRemuzzi, A. Vitamin D, insulin resistance, and renal disease.

Kidney Int. (2007) 71, 96-98.

Current data associates vitamin D deficiency with

multiple disorders (25-OH = Calcidiol deficit)

Cancer

Albuminuria CKD progression

Insulin Resistance

Secondary Hyperparathyroidism

Cardiovascular Disease Carotid thickening

Hypertension

Early mortality Plain/Dialysis

Define Deficiency when PTH elevated??

Vitamin D Deficiency/Insufficiency Rickets Targets

25(OH)D serum levels For Bones only

< 15 ng/mL Deficiency < 37.5 nmol/L

>15, <30 Insufficiency 37.5 -75

≥ 30 ng/mL Replete ≥ 75 nmol/L

25-Hydroxyvitamin D [25(OH)D] /Health

NIH 2012

nmol/L ng/mL* Health status

<30 <12Associated with vitamin D deficiency, leading to rickets in infants

and children and osteomalacia in adults

30–50 12–20Generally considered inadequate for bone and overall health in

healthy individuals

≥50 ≥20Generally considered adequate for bone and overall health in

healthy individuals PTH at baseline in healthy persons

>125 >50Emerging evidence links potential adverse effects to such high

levels, particularly >150 nmol/L (>60 ng/mL)

Who When Supplement Vit D

Everyone Blindly or 25-OH = Calcidiol 50-100Regardless PTHNot as Rx; as Basic nourishmentVDRA’s not enough!!!!Different from Rx VDRA’sRecommended not proven yet

http://drholick.com

Phosphorus as Poison Normal and vital ion

Linked to Protein in food but added

CKDII+ : body keeps balance without high level but at a price : PTH ; tissue deposition

Ca x PO4 = active process like osteogenesis

Remain “Normal” range until late CKDIV

Normophosphemia in CKD NOT ENOUGH

TRP FEPO4 needs monitoring !!!

PhosphorusVery Common 1% weight;

< 0.03 % dialyzableConstituent/chelated/inorganicIntake 800-2700 mg/day (added)Absorption Passive + activeRegulated?Excretion : Renal Regulated by Phosphatonins PTH, FGF23 othersIs there safe limit? MDR?

Phosphorus Additives Dicalcium Phosphate

Hexametaphosphate

Monocalcium Phosphate

Phosphoric Acid

Pyrophosphate

Sodium Acid Pyrophosphate

Sodium Aluminum Phosphate

Sodium Phosphate

Sodium Tripolyphosphate

Tricalcium Phosphate

Why PO4 additivesWorldwide use ; USA 4x increase Leavening • pH Contrrol • Suspension/dispersion agent • Anti caking • Decrease cooking time • Emulsifier • Stabilizer • Moisture binding • Improve texture • Maintain color or firmness • Flavor enhancer

PO4 Absorption is active : Na/PO4 Cotransporter

Inhibiting decreases Na & PO4 absorption Dream pill 2/day

Binders crank up CoTransporter = Do not skip!!

Niacin alone or plus Laropiprant (antiflushing)

Phosphonoformic Acid (Foscarnet)

Others under research

*Adjusted for baseline age, sex, race, cerebrovascular disease, diabetes, ischemic heart disease, HF, acute renal failure, calcium intake from medications, serum calcium, inverse of baseline creatinine, time-averaged creatinine, slope of creatinine, maximal creatinine concentration, and hemoglobin. Baseline CrCl: 39.5 – 50.4 mL/min.Kestenbaum B et al. J Am Soc Nephrol. 2005;16:520-528.

Serum Phosphorus and Mortality Risk in CKD Patients Not on Dialysis

1.001.15

1.32 1.34

1.90

Serum Phosphorus (mg/dL)

5%

88%

7%

1.83

n=6730

1.0

0.0<2.5 2.5-3.49 3.5-3.99 4.0-4.49

Ad

just

ed

Ha

za

rd R

ati

ofo

r M

ort

ali

ty*

4.5-4.99 ≥5.0

2.0

50 40 30 20 1060

Adapted from Kestenbaum B et al. J Am Soc Nephrol. 2005;16:520-528.

Ph

osp

ha

te (

mg

/dL

)

2

3

4

5

6

90 80 70

Cockcroft-Gault Estimated Creatinine Clearance (mL/min)

Trade Off Hypothesis In CKD < V hyperphosphemia rare

Filtered load decreases with decreasing GFR

Diet/ Absorption unchanged:

FEPO4 must increase (TRP decrease)

Phosphatonins (Hormones to pee PO4):

PTH’s

FGF 23

Others under study and synthesis (MEPE)

Trade Off HypothesisBricker NS: NEJM 286: 1093-1099, 1972

Prevalence of Abnormalities of Mineral Metabolism PTH in CKD

(n = 61) (n = 117) (n = 230) (n = 396) (n = 355) (n = 358) (n = 204) (n = 93)

CKD Stage 3

CKD Stages 4 and 5

% o

f P

ati

en

ts

eGFR (mL/min/1.73 m2)

0

10

20

30

40

50

60

70

80

90

100

79-70 69-60 59-50 49-40 39-30 29-20 <20

iPTH >65 pg/mL

Phosphorus >4.6 mg/dL

Calcium <8.4 mg/dL

eGFR = estimated glomerular filtratron rate; iPTH = intact PTH.Adapted from Levin A et al. Kidney Int. 2007;71:31-38.

>80

CV Risk = even non- CKD PO4 correlates

Impaired endothelial function

Renal Interstitial fibrosis / CKD progression

Accelerated Vascular calcification

Phosphatonins can be toxic PTH : Bone , CV, Neuropathy ; associated incr.

Mortality

FGF 23 : LVH, Vascular ; associated incr. Mortality

Others : Not clearly identified

Arterial Calcification is active cell mediated process resembling Osteogenesis; not simply CaxPO4

Which are Calcification mediators??

Dialysis removal PO4 poor Inorganic PO4 added to diet : well absorbed

Constituent Organic PO4 or Chelated (phytate ) little bioavability

Diet restriction should center inorganic added

Binders needed until absorption blockers out

Binders Aluminum Aluminum Hydroxide, Sucralfate

Strongest binders; Constipation

Al+3 Toxicity : Bone , Bone Marrow, Brain

Levels > 50-100 warn; slow > 2-3 years

All toxicity occurred before levels could be measured

Most came from dialysis water with Aluminum

Most nephrologists do not use them but there is role

Binders : Calcium Ca Acetate (Not Citrate) 667 = 169 mg;

Carbonate .5 = 199.6 mg

Rather effective but Silent toxicity

Hypercalcemia rare

Maximum dose ? 3-4 pills day TOTAL Old limits CaAc 9 CaCarb 5 pills

MDR for CKD undefined : very low!!

Do not use if tCa++ > 9.5- 10; PTH< 300; Ion product > 65-70

Interactions : Quinolones, Vit D’s , Thyroid, CCB’s, Tetracyclins

Probability of All-Cause Survival According to Calcification Status

*Comparison Between Curves Was Highly Significant (x2=42.66, P<0.0001)

Blacher A, et al. Hypertension: Vol 38, pp 938-942, October 2001

0 Arteries Calcified

1 Artery Calcified

2 Arteries Calcified

3 Arteries Calcified

4 Arteries Calcified

Pro

babili

ty o

f S

urv

ival

0.00

0.25

0.50

0.75

1.00

Duration of Follow-Up (Months)

0 20 40 60 80

P<0.0001

n = 110

Medial CalcificationIntimal Calcification

Vascular Calcification

Binders: Magnesium Mg Hydroxide, Magnebind (with Calcium

Follow Mg++

Maximum level 3.5-3.8 : toxic

Diarrhea

Directly inhibits PTH

Is that good ?

Consider if Ca++ included

Binders: Sevelamer Sevelamer HCl; Carbonate; others

Weak , more expensive

Drug interaction: Thyroid, Vit D ,E & K, Calcitriol, Quinolones, Tetracyclines

Non Toxic : risk Obstruction

Lower Bad Cholesterol

May improve mortality vs. Ca binders

Binders : Lanthanum Carbonate Second only to Al+3 in power

Soon as powder (homemade also)

Non Toxic

Cost, tolerance

Drug Interactions : Thyroid , Vit D’s , Quinolones, Tetracyclines

Binders: Iron Velphoro = Sucroferric oxyhydroxide =

1 per meal

Higher MW

Auryxia =Ferric Citrate =

2-3 tabs 1 gram each per meal

Lower MW

So far no Al+3 toxicity x 1y exposure

Both GI problems; dark stools. Some iron absorption; may trigger false OBS?

1 84847

37

53

1

47

8

10

15

37

2428

34

43

84

84

84848484

84

84

84

8484

Capture AbDetector Ab or Detector Ab

First-generation IMA

Second-generation IMA

1

Diagram of the multiple species of PTH peptides in the circulation. The major forms are depicted with heavy lines. The grey areas depict the regions of the PTH sequence that are detected by various antibodies for first-generation and second-generation immunometric assays and indicate the PTH peptides that would be detected in each assay. The symbol ( ) depicts a PTH 1-84 peptide that is likely post-translationally modified in a region which interferes with its detection by first-generation immunometric assays.

Circulating PTH Peptides

Normal Uremia

Not all PTH is active only in REDSome blocks PTH action

1-84 PTH "7-84" Mid/C PTH

From Brossard et al Seminars in Dialysis 15: 196, 2002

80%

15%

5%

2%

2%

96%

Klotho allows FGF 23 action

Scientific basis for using VDRA’ s to Rx hyperpara CKDV

“Current vitamin D therapy in ESRD appears largely based on the dramatic responses we described in the 1970s. These responses were seen in an highly selected group of patients with very severe disease. We did not study asymptomatic patients or patients with mild/moderate PTH elevations, patients who make up the bulk of those now treated with calcitriol and its descendants.> So, whether we are harming or benefitting such patients with our current approaches is quite unclear to me. I suspect in these patients, the complications of treatment may well outweigh the benefits”Don Sherrard NEPHROLCochran Collaboration 2009 Issue 4 = no data to support any VDRA more

Many Studies Show a Clinical Advantage for VDRA Therapy

Decrease in mortality: Teng et al., J Am Soc Nephrol. 2005;16:1115-1125 Kalantar-Zadeh et al., Kidney Int. July 2006 Tentori et al, Kidney Int. Oct 2006 Lee et al, J Renal Nutr. 2007 Melamed et al, Kidney Int. March 2006 Young EW et al, ASN Proceedings 2005 TH-PO735 (DOPPS study) Wolf et al., ASN Proceedings 2006 TH-FC 093 Spiegel DM, et al. ASN Proceedings 2006 F-FC080 Schumock et al., ASN Proceedings 2006 SA-PO340 Naves et al., ASN Proceedings 2006 TH-PO977 and TH-PO976 (CORES study) Japanese Society for Dialysis Therapy Ann. Report 1999

Decrease in hospitalizations: Go et al., NEJM 2004; 351: 1296-1305 Dobrez DG et al, Neph Dial. Trans. 2004; 19(5): 1174- 1181 Tentori et al., ASN Proceedings 2006 SA-PO577 Melnick et al, 25th Ann Dialysis Conf. 2005 Proceedings, 9 (1):90-90

What is ahead in pipeline

“Son of Cinacalcet” =R568 2-Chloro-N-[(1R)-1-(3-methoxyphenyl)ethyl]-benzenepropanamine HCl

“Son of Sevelamer” Japan 13 Pt’sChitosan chewing Gum PO4 absorption blockers

Alcohol injection Parathyroids??

More Indirect Studies Few Survival Studies:

IMPACT-SHPT “Paricalcitol or Cinacalcet centered ..markers CKD-MBD” Neph Dial Transp 2014: Feb 4 (Epub)iPTH 300-800 PO4 < 6.5 = Paricalcitol won

What do I do ?Keep reading criticallyNew Binders , PO4 blockersSupplement nutritional VitDAvoid Proton PoisoningCKD Follow PO4 + TRPLimit added inorganic PO4 Binders : Ca/Non CaPTH Rx only if Alk PhosNothing beats steel for PTH ??

Our Job in CKD-MBD

CKD V :Not all Poisons are equal :

High Ca > 10-11 : short term toxicLow Ca Harmless unless Tetany : no need to Rx !! Except hypoparathyroidism

PO4 : Slowly toxic : no level safe ? > 2-2.5 ??Low PO4 marker malnutrition

PTH : Wide range with few toxic effects

Low worse than High still weak poison

K : Acute high > 6 -6.5 ; slow can tolerate better : EKGLow (< 3.5-3.8) predialysis a risk if bath K low

Mg 3-3,5 OK over 4-6 respiratory depression

Al+3 : takes years to build up ; over 100 toxic

And the Emperor was Naked…

Calcitriol = 1,25 Circulating Hormone only made kidney1,25 level important Bone Heath

Aluminum binders not absorbedCorn, Beans are high in PhosphorusControl PTH by high bath Calcium (Ca =3.5)Ca binders good for you: Strong bones /lower PO4

If KT/V OK you are OK = Express Dialysis Vit D analogs will cure PTH; use plentyCinacalcet replaces parathyroidectomyParicalcitol safer than Hectorol or Calcitriol

Nothing beats steel for PTH

My Rx scheme 3/15Do as little harm as possible within ignorance

PTH Ca Binders VDRA's Cinacalcet

< 200 No No No

200-300 OK Yes No

> 300 OK Yes Yes

> 1000 OK Yes ?? Yes ??

tCa Ca Binders VDRA's Cinacalcet9.8-10 No ?? Yes< 9.8 Yes Yes if high PTH Alk>10 No No YesCaveats : Respect Max Ca dose (Antacids ) ; Ca x PO4 < 70; Parathyroidectomy ??Avoid Ca overload > HyperCaRx PTH = Not proven much help to Pt’s but need Chart buffed

Thank you !! Jorge Roman-Latorre MD

ElTote@Hotmail.com

STOP

Slide Show

Toxic Fosfatonins PTH no longer only one:

FGF-23

produced by osteocytes reduce the renal resorption of phosphate,

reduce 1,25 vitamin D levels

suppress PTH levels

“master regulator of the calcium-phosphate cross product,”

CV Toxic ??

Others under study

Trade off Hypothesis Normal SPO4 = 4 mg/dl filters 57600 mg in 24h

excretes 900 = reabsorbs 99%

CKDIV also SPO4 = 4 mg/dl filters 5760 mg in 24h but reabsorbs only 70% or less

Keep SPO4 fairly constant by cutting back reabsorption = trade off

Phosphatonins regulate (PTH, FGF23 ,others)

Management CKD-MBD II 2012

VDRA’s to control overactive/overgrown PTHsNot a simple problem of SS VDRA’s/Cinacalcet/Binders :Calci(fe)diol/Calcitriol/

Paricalcitol/DoxercalciferolCalcimimetics : Cinacalcet/ R568 iv Parathyroidectomy Subtotal/ Total + autograft

ETOH Injection (only Japan)Avoid Low Turnover/Adynamic Bone Dx !!

PTH < 2 x upper limit true hypocalcemia :

DC Calcimimetics, VDRA’s