Dr R V S N Sarma M DConsultant PhysicianTiruvallur 602 001Cell 93805 21221

CHRONIC KIDNEY DISEASE – CKDA Silent Killer

Now we know why the titanic sank !!

< 0.5 %

5- 10%

This is not what we want !!

• Pedal, ankle, facial oedema

• Urine output decreased (romba)

• Lasix is the only weapon

• At best order for bl. urea or creatinine

• We cannot handle it

• Immediately pack off to Dr. RENAL

Practice Guidelines of CKD

The National Kidney Foundation (NKF)

National Kidney Diseases Education Program

The NKDEP

KIDNEY / DISEASE OUTCOMES QUALITY INITIATIVE

The K/DOQI

Why this CME on CKD ?

• CKD is a major global pandemic like DM

• DM and HT make CKD burden very high

• CKD predicts CVD – the major threat

• Testing and therapy are inadequately used

• Knowledge on CKD is at best sketchy

• Testing and early therapy are economical

• Most of the progression is preventable

Do we care about CKD ?

1. Doctors do not realize that CKD is hidden in their

patients of DM, HT and in elderly people

2. Most doctors screen less than 10% of their clinic

patients for CKD in its early stages

3. Patients are referred very late to nephrologists

especially after the CKD is irreversible

4. Only < 1/4 of people with identified CKD get an

ACE Inhibitor – All are true - all over the globe

Filtration, Reabsorption and Secretion

Normal GFR 120 ml/min/1.73m2

Only 20% nephrons work at a time

In a day 210 L of water is filtered

2 L /day of urine is excreted

Prevalence of CKD

What is the role of GPs ?

1. Recognize who is at risk of CKD

2. Consider all DM and HT as potential CKD pt.

3. Evaluate all at risk cases; treat hypertension

4. Understand eGFR, Albuminuria, MAU

5. Stage the CKD and manage appropriately

6. Must start patients on ACEi or ARB early

Some useful Definitions

1. Azotemia - Elevated blood urea nitrogen - Biochemical (BUN >28 mg/dl) and creatinine (Cr >1.5mg/dl)-

2. Uremia is Azotemia + symptoms or signs of renal failure

3. End Stage Renal Disease (ESRD) - Uremia requiring transplantation or dialysis (Renal replacement therapy)

4. Chronic Renal Failure (CRF) - Irreversible kidney dysfunction with azotemia >3 months – now not used

5. Creatinine Clearance (CCr) - The rate of filtration of creatinine by the kidney (a marker of GFR)

6. Glomerular Filtration Rate (GFR) - The total rate of filtration of fluid from blood by the kidney

Clinical Features – CKD 3-5

• Unintentional weight loss

• Nausea, vomiting General ill feeling

• Fatigue; Headache; Frequent hiccups

• Generalized itching (pruritus)

• Increased or decreased urine output

• Need to urinate at night, polyuria

• Easy bruising or bleeding

• Blood in the vomit or in stools

• Decreased alertness; Muscle cramps

• Seizures; Agitation; Hypertension

• Peripheral sensory neuropathy

• Breath fetor; Loss of appetite;

• Uremic frost on the skin

• Uremic pericarditis, CHF

Clinical Features – CKD 3-5

Who are at Risk for CKD

• Diabetes• Hypertension• Age , Family H/o Kidney Disease• Systemic Infections• Recurrent UTI• Urinary Stone Disease• Loss of Renal mass• Neoplasia of any part• Nephrotoxic Drugs (NSAIDs)

Risk of CKD is not uniform

Racial differences in CKD

Caucasians (Whites) 1.0

Asians (Indians) 1.3 X

Hispanics (Spanish) 1.5 X

Native Americans 2.0 X

Africans (Blacks) 3.8 X

Etiology of CKD

1. Diabetes - most common cause ESRD (risk 13 x )

2. Over 30% cases ESRD are primarily due to diabetes

3. CKD associated HTN causes @ 23% ESRD cases

4. Glomerulonephritis accounts for ~10% cases

5. Polycystic Kidney Disease - about 5% of cases

6. Rapidly progressive glomerulonephritis (vasculitis) - about 2% of cases; Drug induced Tubulo-interstitial

7. Renal Vascular Disease - renal artery stenosis (ARAS), atherosclerotic vs. fibromuscular

The Two Most Common Causes of CKD

Primary Diagnosis for Patients Who Start on Dialysis

Diabetes

50.1%

Hypertension

27%

Glomerulonephritis

13%

Other

10%

Causes of CKD

CKD Predicts CVD

2.113.65

11.29

21.8

36.6

0

5

10

15

20

25

30

35

40

≥ 60 45-59 30-44 15-29 < 15

Estimated GFR (ml/min/1.73 m2)

Ca

dio

-va

scu

lar

ev

ents

p

er

100

0 p

ers

on

y

ears

Definition of CKD

1. Either GFR < 60 ml/min/1.73m2 for 3 mon or

2. Kidney damage for 3 mon as manifested by

a. Persistent microalbuminuria / macroproteinuria

b. Biochemical abnormalities in RFT

c. Persistent non-urological hematuria

d. Structural renal abnormalities by USG

e. Biopsy proven Glomerulonephritis (rarely needed)

(Any one of the above evidences)

CKD Clinical Stages

Stage Description GFR (ml/min/1.73 m2)

1 Kidney damage with normal or ↑ GFR 90

2 Kidney damage with mild GFR 60-89

3 Kidney damage with moderate GFR 30-59

4 Severe GFR 15-29

5 Kidney Failure (ESRD) < 15 (or dialysis)

CKD PrevalenceChronic Kidney Disease - Stages

K/DOQI CKD Staging

CKD Features – Stage wise

CKD eGFR B.P ACR Urine Edema Anemia Ca x P SHPT

Stage 1

>90 N MAU N No No N No

Stage 2

60+ ↑ MAU ↑ No N No

Stage 3

30 + ↑ ALB ↑ No N

Stage 4

15+ ↑ ALB ↑↓ ↑ ↑

Stage 5

<15 ↑↑ ALB ↓ ↑ ↑

GP and Nephrologist in CKD

Who is to be tested for CKD ?

Regular testing of people for CKD a must for

1. All Diabetics whether Type 2 or Type 1

2. All Hypertension patients – SHT or DHT

3. Patients having a relative with kidney problem

4. All patients of Cardiovascular disease

5. Pts of Obesity, Metabolic syndrome, smokers

Investigating CKD

Blood Urea v/s Sr. Creatinine

Parameter Blood Urea (BUN) Serum Creatinine

As measure of GFR Only half the GFR Nearly 95%

Calculation of eGFR Not useful It is the parameter

Day to day variance More Less

Pred. of improvement Changes late Changes soon

Affect of meat diet Yes; affected Yes; affected

Volume status of pt. Affects very much Not so much

Upper GI bleeding Increases it Not affected

Corticosteroid Rx Increases it Not affected

The Two Imp. Tests for CKD ?

1. Test serum creatinine; Note age and gender

2. Estimate GFR from serum creatinine (MDRD)

3. Standard dipstick for urine protein – if negative

4. Spot urine Albumin to Creatinine Ratio (ACR)

5. 24 hour urine collections are NOT needed.

6. Diabetics should be tested at least once a yr.

7. Others at risk to be tested once in 2 years

Today’s Watch Word

At what level of Serum Creatinine would you diagnose CKD?

• In a 65 years old lady of 50 kgs with DM and HT

• 87% of doctors said Creatinine > 1.5 mg /dl

If Sr. Creatinine is 1.0 mg%

The eGFR will be 59 ml/min/1.73 m2

If Serum Creatinine is 1.5 mg %,

The eGFR = 37 ml/min/1.73 m2

Creatinine clearance is 35 ml/min

Methods of GFR Estimation

• Inulin / I125-Iothalamate clearance is

the “Gold Standard’

• Creatinine Clearance (24 h urine)

• Equations based on serum creatinine

– MDRD (age, sex, ethnicity)

– Cockroft-Gault (need weight also)

Why eGFR ? Why not Creatinine ?

CCr and eGFR Correlation

eGFR calculation

Don’t be afraid – we have help

Albuminuria andMicroalbuminuria

How to test for MAU ?

Albumin Creatinine Ratio (ACR)

Spot urine only (no 24 hour urine)

Urine Microalbumin in mg/liter

Urine creatinine in mg/deciliter

ACR calculation :

Urine MAU in mg/l 60

Urine creatinine mg/dl 120 X 100 = X 100

= 50

Interpretation of Albuminuria

Spot Urine only

(No 24 hr urine please)

Albumin : Creatinine Ratio (ACR)

(Urine albumin in mg per liter ÷

Urine creatinine in mg/dl) x 100

No Albuminuria Less than 30 mg/g

Micro Albuminuria 30 to 300 mg/g

Macro Albuminuria More than 300 mg/g

Nephrotic Proteinuria More than 3000 mg/g

MICRAL Test II Strips for MAU

• RDT – Bed side• Sensitivity 95 %• Specificity 85 %• PPV 89%• NPV 92%• Sp. Gr. Correction• Cost Rs.84/- strip• Simple reliable

Roche

Imp. of Albuminuria in CKD

Treatment of CKD (contd..)

1. Renal diet with adequate protein, salt, H20

2. Consult a nephrologist early (from stage 3)

3. Team with the nephrologist for care if eGFR is less than 30 ml/min/1.73 m2

4. Monitor hemoglobin and sr. phosphorous

5. Treat cardiovascular risk factors, especially smoking & hypercholesterolemia

Metabolic Effects of CKD 3-5

1. Hyperkalemia

2. Mixed Metabolic acidosis

3. Fluid loss/ Fluid over load (Stage 5)

4. Hyponatremia or Hypernatrimia

5. Normocytic normochromic anaemia

6. Increased Ph, ↓ Calcium

7. ↓ Vitamin D formation

8. Secondary ↑ in PTH

9. Renal Osteodystophy

How to handle CKD ?

• A A1c < 6.5, ACEi, ARBs• B Blood pressure < 125/75• C Cholesterol LDL < 100• D Drugs – avoid nephrotoxicity

Diet – Moderate in protein

Na, K, Ph, Fluids, Cal

CKD – Management Goals

1. Blood pressure < 125/75– HT is both a cause and consequence

2. Glycemic control – Hb A1c < 6.5

3. Hemoglobin level > 11 g%

4. Calcium x Phosphorous product < 50Normal values :

GFR 120 to 150 ml/min/1.73m2

Ca 9 to10.5mg%, Ph 3 to 4.5mg%, Ca x Ph < 50

iPTH 150 to 300 pg/ml

Early treatment makes a difference in CKD

Brenner, et al., 2001

B.P. Treatment in CKD

1. Maintain B.P. less than 125/75 mmHg

2. Use ACE Inhibitor or ARB early enough

3. More than one drug is usually required

4. Diuretic should be part of the regimen

5. Achieve best possible glycemic control in Diabetics

The Renal Injury (CKD) Triad

Angiotensin II

ProteinuriaHypertension

*Primary end point: doubling of SCr or kidney failure.

Nakao et al. Lancet. 2003;361:117-124.

ACEIs, ARBs, and Combination RX. in Non-diabetic Nephropathy

P = 0.02

ACEI + ARB (n = 88)

Losartan (n = 89)

ACEI (n = 86)

© 2005 The Johns Hopkins University School of Medicine.

Importance of control of DM

DM and Proteinuria

CKDdeathCKDdeath

Stages in Progression of Chronic Kidney Disease and Therapeutic Strategies

ComplicationsComplications

Screening for CKD

risk factors

CKD riskreduction;

Screening forCKD

Diagnosis& treatment;Rx. comorbidconditions;

↓ progression

Estimateprogression;

Rx. complications;Prepare forreplacement

Replacementby dialysis

& transplant

NormalNormal Increasedrisk

Increasedrisk

KidneyfailureKidneyfailureDamageDamage GFR GFR

Stage-wise management of CKD

Stage 0 Test for CKD, Management of Risk Factors

Stage 1 Manage co-morbidity, Rx. of CVD and RF

Stage 2 Slow rate of loss of Kidney function - ACEi

Stage 3 Prevent Anemia, Bone effects, Ca x Ph

Stage 4 Preparation for RRT; refer to nephrology

Stage 5 RRT – PD, HD or RT – Donor / Cadavre

Effects of Good Glycemic Control Reduces Complications

DCCT = The Diabetes Control and Complications Trial.DCCT Study Group. N Engl J Med. 1993;329:977-986; Ohkubo. Diabetes Res

Clin Prac. 1995;28:103-117; UKPDS Study Group. Lancet. 1998;352:837-853.

© 2005 The Johns Hopkins University School of Medicine.

Recommendations for BP andRAS Management in CKD

Expect the need to use 3+ agents to chieve B.P. goalsRecommendations largely consistent across JNC 7, ADA, and K/DOQI

© 2005 The Johns Hopkins University School of Medicine.

Macroalbuminuria in T2DM Heralds Rapid Decline in GFR

-50

-40

-30

-20

-10

0

1 1.5 2 2.5 3 3.5 4

Time yearsC

hang

e in

GFR

ml/m

in

Microalbuminuria

Macroalbuminuria

Nelson RG. et al NEJM, 1996

Diabetics with MAU are more likely to CV death than develop ESRD

CV

DEATHElevated Serum Creatinine

19%

No albuminruia1.4%

2.0%

Microalbuminruia3.0%

2.8%

Macroalbuminruia4.6%

2.3%

The United Kingdom Prospective Diabetes Study (approx. 5000 Type 2 Diabetics) Newly diagnosed, predominantly white, medically treated

Adler et al. Kid Int, 2003

Diabetic Nephropathy

Diabetic Nephropathy

Diabetic Nephropathy

• Lower blood pressure < 125 / 75 mmHg

• Reducing Proteinuria

• Combination of ACEi + ARB

• Multiple risk factor intervention

– Glycemia

– Dyslipidemia

– Physical activity

– Aspirin

– Smoking cessation

Adverse Renal and CVEffects of Aldosterone

Glomerulosclerosis

Interstitial Fibrosis

Proteinuria

Renal Failure

LVH

Cardiac Fibrosis

LV Dysfunction

Heart Failure

Endothelial dysfunction

Inflammation

Oxidative Stress

Aldosterone

MRA – EplerenoneBrand name: Eplirestat

Ang I

Ang II

Progressive Diabetic Nephropathy

ACE

Renal Injury and Proteinuria

ACEi

AT1 Receptor

Non-ACEPathways

Aldosterone

MRAMRA

ARB

Dual Blockade of the RAASin Diabetic Nephropathy

+

+

Hb < 11.3*

Hb > 13.8

Hb 12.5-13.8*

Hb 11.4-12.5*

Time, in years

4321

En

d-s

tage

ren

al d

isea

se, %

10

20

50

60

30

40

0

Baseline Hemoglobin Predicts ESRD in Type 2 Diabetics with Nephropathy:

RENAAL Trial (N=1513)

Mohanram et al. Kid. Int. Sept 2004

-1.00> 13.8

0.0021.8512.5-13.8

0.021.6111.3-12.5

0.0011.99< 11.3

P value

Adjusted HR*

Hb g/dl

* Age, gender, GFR, Race, Proteinuria,CV disease, A1c, lipids, BP, Ca, P, albumin

Diabetic Nephropathy Some Novel Therapies

1. Pirfenidone –antifibrotic agent

2. Aliskerin – an anti-renin agent

3. Robuxistaurin- Protein Kinase C

Beta-1 antagonist (PKCB1-A)

4. Advanced Glycation End product

(AGE) antagonists

Diabetic Nephropathy Management Summary

Anemia is an Important CV Risk Factor in CKD

Chronic Kidney Disease

Cardiovascular disease

Anemia

Anemia in CKD

• Decreased production– Low EPO (RF)– Nutritional

• (Iron, B12, Folate)

– inflammation – Infection, Ca

• Blood Loss• Serum Erythropoietin

levels not indicated

• Reticulocyte count• Red Blood Cell

indices: MCV, RDW• Iron Parameters

– TIBC– Serum Ferritin

• Vitamins:– Folate\B12 levels

• Stools for occult blood

Principles of Anemia Rx.

• Erythropoietin– Epoetinalfa - Procrit® , Epogen® – Darbepoietin Alpha - ARANESP ®

• Targets– Hb 11 to 12 g/dl– PCV 33% to 36%

• Iron supplimentation to maintain– TSAT of >20%, – Serum ferritin level of >100 ng/ml

Feedback Loops in SHPT

Ca = calcium; CVD = cardiovascular disease; P = phosphorus. Courtesy of Kevin Martin, MB, BCh.

PTH

Bone DiseaseFracturesBone pain

Marrow fibrosisErythropoietin resistance

Serum P1,25D

Calcitriol

Renal Failure

PTH

Systemic ToxicityCVD

HypertensionInflammationCalcification

Immunological

25D

Ca++

Decreased Vitamin D Receptors and Ca-Sensing Receptors

Vitamin D and PTH in CKD

Calcium & Phosphorus Balance

• AIM - To Normalize– Serum calcium

– Serum Phosphorus

– PTH levels

• Methods– Oral Calcium; Vitamin D analogs

– Phosphate binders (sevelamer-Renagel®)

– Calcimimetics (cinacalcet-Sensipar®)

Phosphate Control

• Dietary restriction of phosphorous• Phosphate binders to ↓↓ absorption

– CaCo3 ( BoneStat)– Ca acetate (PhosLo)– Sevelamer (RenaGel)– Al hydroxide, Al carbonate– PhosRenal (Lanthanum Carbonate)

• Removal of Ph by dialysis - poor

Phosphate: Restriction

Special Treatment in CKD

Calcium acetate (PhosLo) 1334 mg PO with each meal

Calcium CrabonateSandocal, Bonestat, Oyestercal, Cipcal 1-2 g bid with each main meal

Calcitriol (Vitamin D), Paricalcitriol0.25 mcg PO once a day

Doxercalciferol (Vitamin D analog)10 mcg PO x 3 times a week

Special Treatment in CKD

Sevelamer (RenaGel) – 800 to 1600 mg PO with meal

Calcimimetics – Cinacalcet - ↓ PTHSensipar orally with meal30 mg PO once day – up to 120 mgPTH target of 150 to 300 pg/ml

Eplerenone (Selective MRA)Eplaristat

Lanthenum Carbonate (FosRenal)250 to 500 mg tid to be chewed

Fluids in CKD – Wet?

High Energy Foods: Yes

Protein 0.6 g per kg

Some Simple Salt Rules

• Do not add salt to your food at the table.

• Do not use flavoured salts, e.g. garlic salt or sea salt.

• Use only a small amount of salt in cooking or none.

• Do not use salt substitutes, e.g. Lo Salt or LONA

• Use herbs, spices and other flavorings agents

• Pickles, tinned foods, tinned juices, chips, savories, papads, salted fish, sea foods are rich in sodium

• Recommended salt in take is less than 2 grams /day

Na: 1.5 to 2.5g (4.5 to 6)

Potassium Liberal

Low Potassium Diet !

Low Potassium Diet

Important Guidelines

Interventions to slow progression of CKD

1. Glycemic control in DM

2. BP control ACEI / ARB

3. Protein restriction

4. Lipid lowering therapy

5. Weight reduction

6. Anemia Rx, Smoking

To be avoided to prevent acute reduction in GFR

1. Volume depletion

2. Radiographic contrast

3. Antibiotics / NSAIDS

4. Cyclosporine / tacrolimus

5. ACEI / ARB if Cr > 3.5mg

6. Obstructive uropathy

Preparation for RRT

• Choice of Renal Replacement• Timely Access Surgery• Timely Dialysis initiation• When GFR < 25ml/min

– Renal transplant is the first choice– Workup living donors– If no donors available– List patient on cadavre transplant list– Place A-V fistula if HD preferred

Peritoneal Dialysis

• CAPD – Continuous Ambulatory PD

• CCPD – Continuous Cycling PD

• PD catheter placement by LAP

• URR – Urea Reduction Ratio – 65%

• Kt/V (Kay tee over vee) – at least 1.2

• Tests done monthly

Peritoneal Dialysis (PD)

A-V Fistula Access

Hemodialysis

Indications for Hemodialysis

Absolute indications (Chronic) • GFR < 15 ml – Stage 5• Creatinine > 8, BUN >100• K > 7.0 meq persistently• Refractory CHF, Diuretic F• Accelerated Hypertension• Uremic pericarditis• Uremic encephalopathy• Uremic Bleeding, Vomiting

Acute indications• Poisoning - dialysable• Drug over dosage• ARF > 48 hours• GFR < 30 ml• Metabolic acidosis• Hyperkalemia• Hyperphosphatemia

Nephrotoxic Drugs

• Which drug is (not) nephrotoxic?– Antibiotics

• Aminiglycosides, Indinavir, Amphotericin• Penicillin / -lactums, Tetracyclines • Fluoroquinolones, Sulphas, Ketoconozole gr.

– NSAIDS/ COX2 inhibitors, Indometh. Nimesulide– Cancer: MTX, Cisplatin, Acyclovir, Pentamidine– Heavy metals: Hg, Pb, Ar, Bi, Lithium– IV Contrast dyes– ACEi / ARBs if Serum creatinine > 3.5

Mechanism of Nephrotoxicity

• Mechanisms of renal toxicity1. Direct injury to PCT, Glomeruli

2. Allergic interstitial nephritis

3. Crystallization in renal tubules

4. Fluid over load on the kidney

5. Renal papillary necrosis

6. Metabolites may be toxic

7. Side effects may increase in renal failure

1. Adequate fluid intake is essential2. Dehydration must be avoided3. Reducing the dosage or avoiding the drug

Let this not happen please!

Normal ESRD

Polycystic Kidney Disease

Contracted Kidneys

Contracted smooth kidney

Scarred kidney –cut section

End Stage Renal Disease

Chronic Contracted Kidney

PCKD with ESRD

My dear Doctors - Remember

Please Remember

Web links for CKD

1. www.kidney.org

2. http://nkdep.nih.gov

3. www.kdoqi.nih.gov

4. www.kidney.org.au

5. www.renal.org/eGFR

6. www.nephron.com

7. www.medicalc.com

8. www.edren.org

1. NKF – USA

2. NKDEP – USA

3. K/DOQI Guidelines

4. Kidney Health- Au

5. eGFR calculators

6. Kidney resources

7. Medical calculators

8. Diet in CKD

Take Home Messages

• CKD is a silent killer – we need to uncover it

• CKD progression is preventable – Stage it & treat

• DM most common cause of ESRD all over globe

• CKD - more likely CV death than progress to ESRD

• Multi-risk factor intervention is critical, Hb A1c goal

• Lowering blood pressure with RAAS blockade

• Combinations of ACEi + ARB ± MRA

• Prevent cardiovascular morbidity and mortality

Thank You All