1

:

2

,

(metabolic

acidosis) (hyperK,

hypocalcemia & hyperphosphatemia

hyperparathyroidism)

3

Confusion, Insomnia, Depression

CVD

Anemia Hyperpigment, Pruritus

Bone disease

Infertile, loss of libido

N/V, Anorexia

Polyneuropathy

Acid/base, , Fluid- imbalance

,

HCTZ, furosemide, spironolactone

5

> 100

6

(metabolic acidosis)

parathyoid hormone (PTH)

7

8

(metabolic acidosis)

sodium

bicarbonate

9

Sodium bicarbonate

GI pH

enteric coated formulation

10

Hyperkalemia

ion exchange resin potassium

Calcium polystyrene (Kalimate

-

-

11

Hyperphosphatemia

2 hyperparathyroidism

osteodystrophy

anemia

HTN

calcification in vascular or soft tissue

CVD

12

13

Bone marrow fibrosis decreased erythropoiesis

14

Aluminium-based : aluminium hydroxide

Calcium-based : calcium carbonate, calcium acetate, calcium

citrate

Aluminium- and calcium-free phosphate binders

: sevelamer, lanthanum

15

PTH

calcification

16

calcium level mg dL calcium based phosphate binder

noncalcium nonaluminium based

phosphate binder

calcium level mg dL

PTH pg mL

Ca x PO > 55 mg2/dl2

vascular

calcification

soft tissue calcification

calcium based phosphate

binder

phosphate level

mg dL

Ca x PO > 55 mg2/dl2

aluminium based phosphate binder

17

Hyperparathyroidism ( iPTH > 300 (500) pg/ mL)

1. Correct calcium and phosphate level

2. Vitamin D or vitamin D analogue

- 1,25- -dihydroxyvitamin D3 (Calcitriol)

- vitamin D analogue: 1- -hydroxyvitamin D3

(alfacalcidol)

- iPTH

- Adverse effect: hypercalcemia, hyperphosphatemia

( ./ . *

( ./ .

( .2/ .2

(

/

K/DOQI

CKD 3 2.7 4.6 8.4 10.2 - 35 - 70

CKD 4 - 70 110

CKD

/dialysis

3.5 5.5 8.4 9.5 < 55 150 300

KDIGO

CKD G5/G5D Normal range Normal

range

- 2-9 * Normal

range

150 600 18

19

20

21

Conclusion: Alfacalcidol can be used to control secondary hyperparathyroidism at doses of 1.5 2.0 times that of calcitriol.

The two drugs are equally and lead to similar changes in calcium and phosphorus.

Nephrology 16 (2011) 277 284

22

Insufficient EPO

Iron deficiency

Hyperparathyroidism

Inflammation or

infection

Inadequate dialysis

Aluminium toxicity

Vitamin B12 or folate def.

Shortened red cell survival

Carnitine deficiency

ACEI

Hyporesponse to EPO

Erythropoietin

24

Prim Care Clin Office Pract 2008;35:329 44. Semin Nephrol 2006; 26:313-8.

Continuous Erythropoietin Receptor Activator

Erythropoiesis stimulating agents: ESAs

Continuous Erythropoietin Receptor Activator(CERA)

26

Hgb

20-50 IU

- EPO-alfa

EPO-beta)

IV SC

erythropoietin

ESA dose > IU/

Hgb

ESA

28

Adverse Effects of ESAs:

Flu like symptom (first use)

Hypertension

Increased risk of cardiovascular events;

heart attack, HF, blood clots, stroke and

death.

Pure red cell aplasia (PRCA)

Seizure

Kidney International 2008;74(Suppl 110):S12 S18.

29

ESAs:

30

: ferrous sulfate, ferrous fumarate

- elemental iron 200 mg/d

- malabsorption, intolerance (N/V, constipation),

noncompliance, excessive blood loss

31

32

Composition

Molecular size

Degradation Kinetics (rate of iron dissociation from

the complex)

Side effect profiles

anaphylaxis, anaphylactoid (iron dextran)

Test dose (25 mg IV infusion)

33

Comparison of intravenous iron products

Products

Properties

Iron Dextran

Sodium Ferric Guconate Complex (SFGC)

Iron Sucrose

Molecular size

(Kilodaltons) Low MW ~ 96

High MW ~ 267 ~ 38 ~ 43

rate of iron

dissociation from the complex

slow rapid

intermediate

Bloodstream t1/2

(hr) 40-60 1 6

Modified from Yee and Besarb AJKD 2002; vol 40 (6): 1111-1121

and P&T News September/October 2001 Virtual Hospital

34

traditional risk factor

nontraditional -related risk factor

Risk factors of CVD in CKD

Share etiology

Prevention and Treatment

BP < 140/90

BP < 1 / 0

nondipping

Noctural long acting Anti-HTN

PREFER RAS inhibitors

Anti-HTN drugs

ACEI: captopril, enalapril, ramipril

ARB: losartan, valsartan

Beta-blocker: propranolol, atenolol (unchanged renal

excreted ~ 40 %) metoprolol, carvedilol

CCB: nifedipine, amlodipine, felodipine

Alpha-blocker: prazosin, doxazosin

Vasodilator: hydralazine, minoxidil

39

statin HD patients 4D

AURORA

Subgroup analysis non-dialysis

patients JUPITER, ASCOT-LLA, CARE

HPS

Participants: NondialysisCKD (M: Scr > 1.7 mg%; F Scr > 1.3 mg%,

HD, PD patients Beneficial for nondialysis patients only

Statins

(primary prophylaxis)

50

50

42

:

43

44

45

:

46

47

Susceptibility Increased susceptibility to kidney damage

Advanced age

Reduced kidney mass and low birth weight

Racial/ethnic minority

Family history

Initiation Directly initiate kidney damage

Diabetes mellitus

Hypertension

Glomerulonephritis

Drug toxicity

Urinary stone

Autoimmune disease

Progression Cause worsening kidney damage and faster decline in

kidney function after initiation of kidney damage

Glycemia (among diabetic patients)

Hypertension

Proteinuria

Smoking

Obesity

47

CKD Risk Factors

Service plan

50

BP Control Prevents CKD Progression

GFR Decline

(mL/min/y)

0

-2

-4

-6

-8

-10

-12

-14

MAP (mm Hg)

95 98 101 107 104 110 113 116 119

r=0.69; P

Proteinuria Dipstick: Semi-quantitative testing

52

Definition of Albuminuria

Normoalbuminuria Moderately increase

albuminuria (Microalbuminuria)

Macroalbuminuria

(Nephropathy)

Detected by

dipstick

No No

(Yes, new

dipstick)

Yes

Urine Albumin

(mg/day)

< 30 30-300 > 300

Urine

Albumin-to-

creatinine

ratio, ACR

(mg/g Cr)

< 30 30 299 > 300 mg

Renal Risk No Marker of future nephropathy

Marker of

progressive

renal disease

53

Development of Macroalbuminuria Heralds Rapid

Decline in Glomerular Filtration in Type II Diabetes

-50

-40

-30

-20

-10

0

1 1.5 2 2.5 3 3.5 4

Time years

Ch

an

ge

in

GF

R m

l/m

in

Microalbuminuria

Macroalbuminuria

Nelson RG. et al NEJM, 1996

54

Proteinuria Dual Significance

Proteinuria results from injury to glomerular

circulation

Increased proteinuria is associated with

progressive CKD

In diabetes and hypertension, proteinuria

signifies injury to the systemic circulation

Proteinuria is associated with increased CV risk

55

Development of Nephropathy

Jamison, Wilkinson. Nephrology, 1997.

TGF- : transforming growth factor TIMP: tissue inhibitors of metalloproteinases PAI plasminogen activator inhibitor

TGF- 1, TIMP-1, TIMP-2, PAI-1

Modification of CKD progression factors

MODIFICATION of RISK FACTORS

INTERVENSION GOAL

1. Hypertension Anti-HTN (prefer ACEI or ARB) albuminuria

mg/day

albuminuria < 30 mg/day

(need more data from SPRINT; be expected 2018)

Salt restriction < 1.5 g/day

2. Proteinuria Anti-HTN (prefer ACEI or ARB)

< 0.5 g/day

3. Hyperglycemia Tight glycemic control HgbA1C < 7 % CKD stage 4/5 < 8 %

Modification of CKD progression factors

MODIFICATION of RISK FACTORS

INTERVENSION GOAL

4. Dyslipidemia lipid lowering Therapy

LDL < 100 mg/dL

5. Protein load Protein restriction 0.8 g/kg/day in GFR < 30 mL/min/1.73 m2

6. Others:

smoking cessation, weight loss (if obese), sleep apnea, correction

or prevention of metabolic acidosis, nephrotoxic drug

avoidance esp. NSAIDs, prevent CVD, AKI

Ongoing or Further Studies

Endothelin anatagonists (avosentan, atrasentan)

Lowering serum uric acid level (uric acid

promote interstitial inflammation, inhibit endothelial nitric

oxide release, stimulate RAAS)

Anti-fibrotic agent

Pirfenidone interrupt transforming growth factor -B pathway

Doxycycline inhibit matrix metalloproteinases

Vitamin B target advanced glycation end products

59

Renin-Angiotensin System (RAS)

CAGE

Cathepsin G

Chymase

adapted from: Chung, Unger., Am J Hypertens 1999;12:150S 156S

CAGE: chymostatin sensitive AngII - generating enzyme

ONTARGET: The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial

Will an ARB (telmisartan) be as effective and better tolerated?

Is the combination superior?

N Engl J Med 2008; 358:1547-1559

Reasons for Permanently Stopping Study Medications

Ram

N=8576

Ram + Tel

N=8502

Ram + Tel vs. Ram

RR P

Hypotension 149 406 2.75

Summary for RAS inhibitor

Normotensive DM patients

macroalbuminuria or microalbuminuria

should be treated with ACEI or ARB.

normoalbuminuria: ACEI/ARB not recommended

Combined RAAS blockade therapy not

recommended

AJKD 2012; 60(5): 850-866

ACEI/ARB

Evidence-Practice GAP undertreated

66

ACE/ARB

Check Cr and K+ within 7-14 days

Cr rise < 30% BP not achieved

No hyper K

Cr rise > 30%

STOP drugs

assess for bilateral RAS

Increase ACEI dose

Hyper K+

mild severe

Low K+ diet

Initiation of ACEI/ARB treatment

67

AKI (ARF) Prevention

Rationale

CKD pts at higher risk for AKI

AKI produces residual kidney damage

AKI often preventable

e.g. vol depletion, drug induced

nephropathy

PA McCullough, et al. Am J Med. 1997;103:368 375

L Gruberg, et al. J Am Coll Cardiol 2000;36:1542 1548

1. 25 %

cardiac output

ischemia

2.

3. 68

Nephrotoxicity from NSIADs

Acute or chronic renal impairment

Incidence of renal side effects - around 1 5 %1

1 Am J Med. 1999;106(5B):13S24S.

Clinical manifestations

Acute Kidney Injury (AKI)

Tubulointerstitial nephritis

TIN

Renal papillary necrosis

Salt Retention and Edema

Hyperkalemia

Hypertension

Worsening of Chronic

Kidney Disease (Acute on

CKD)

70

71 TAL: Thick ascending limb of Henle

- Renal

hypoperfusion

- Salt and water

retention

- Hyperkalemia

PGE2: Afferent arteriolar

Vasodilatation Increased GFR

Inhibition of TAL Na+, K+-ATPase

Inhibition of ADH in the collecting duct

PGI2: Afferent arteriolar

vasodilatation Efferent arteriolar

vasodilatation Increased GFR Release of renin

72

renal cortex

- mononuclear

infiltrate

tubules

- inflammation and

edema

Acute reversible pre-renal failure

(inhibition of renal vasodilatatory PGS)

Risk factors

History

HF (3.37: 2.04-5.58), hypertension (1.94: 1.2-3.13),

diabetes (2.22: 1.31-3.78), hospitalizations in the

previous year (1.61: 1.01-2.57) and consultant visits in

the previous year (3.00: 1.8-4.99)

Current medication

Antihypertensive drugs (5.16: 2.36-11.25), diuretics

(2.77: 1.49-5.12), ACEI (3.46: 2.05-5.85), oral steroids

(2.67: 1.25-5.67) Am J Kidney Dis 45:531-539.

NSAIDs cardiovascular risk

Hypertension (increase mean BP 5 mmHg1, increase mean BP 14 mmHg in hypertensive patients2)

Hypertension stroke, MI, heart failure,

Hypertension, heart failure renal impairment

Diclofenac threefold increase in cardiovascular risk3

1 Drug Saf 17:277 289, 2 Cardiol Rev 19: 184 91, 3 BMJ 342:c7086

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