Chronic kidney disease and the benefits of early detection - PowerPoint Presentation

Slide1

Chronic kidney disease and the benefits of early detection

Dr. T. A. L.

Dlamini

Specialist Physician and

Nephrologist

Slide2

Talk overview

Kidney function

Assessing kidney function

Chronic kidney disease (CKD)

Benefits of early detection

Conclusion and take home message

Slide3

Kidney function

Fluid balance Blood pressure control Acid-base balance Electrolyte balance Endocrine – one alpha Vitamin D hydroxylation-> Calcium re-absorption and Others Erythropoeitin – erythropoeisis – red blood cell production Drug excretion

About 1 million

nephrons per kidney – the filtering units

Kidneys receive 25% of cardiac output

& about 120

litres

/minute of blood is filtered (180litres/24 hours)

Slide4

Assessing kidney function

Good history and

examination – looking for underlying causes and effects

Glomerular

filtration

rate assessment

– rate of passage of blood through the kidneys to enable filtration

2. Urine analysis

3. Renal/collecting system imaging

4. Renal vasculature assessment

5. Kidney biopsy

Slide5

Assessing kidney function

Glomerular

filtration

rate (GFR)

Ideal marker should be one that is not

metabolised

and not altered by the kidneys

Creatinine

(helpful as part of

GFR

calculation but not alone)

- widely used surrogate marker

- derived from muscle

creatine

(a muscle energy store), by enzyme

creatine

kinase

- excreted largely unchanged by kidneys but there is some tubular secretion

- therefore reflects muscle mass (+ dietary meat intake + small amount from tubular secretion)

- so serum

creatinine

of 90

μ

mol/l in a 30 year old 45kg woman is too high, but not bad in a 96kg, muscular 35 year old

man

Cystatin

C (helpful as part of

GFR

calculation)

-

a low molecular weight

cysteine

proteinase

inhibitor

- produced by all n

ucleated

cells

and found in body fluids

- not affected by muscle mass, diet or drugs

Slide6

Assessing GFR in clinical practice

All prediction equations require a steady state for interpretation – ie not great in acute kidney injury or pregnancy

Equation

Cock-Croft

Gault

Equation

Modification

of Diet in Renal Disease (M

DRD) study equation

Chronic

Kidney Disease Epidemiology Collaboration (CKD-EPI) equation

CKD

epi

creatinine-cystatin

equation

Formula

Creatinine

based

Adjusted for age, weight,

and

female sex

Creatinine

based

Includes age, male,

Black ethnicity, & adjustments for urea & albumin

Creatinine

based

Includes age,

female sex, Black ethnicity

Creatinine

and

cystatin

based

Disadvantage

was tested in Caucasians

, not Black race

Not validated in children,

pregnancy

Not validated in elderly as still

creatinine

based

More

accurate than only

creatinine

based equations

Advantage

Simple calculation,

can help guide drug dosing

Validated for African Americans, Black

South

africans

,

diabetics,

renal transplant

Better for patients

with higher GFR

> 60ml/min

Useful

at confirming CKD in GFR 45-59 with no other evidence of kidney

Slide7

Urine analysis

Method of urine analysis

Pros

Cons

Visualisation

Naked eye

appearance

Measurement of volume

Food dyes

eg

beetroot, contamination durin

g menstrual cycle

Standard dipsticks

1+ = >300mg/24hrs

urine albumin

Can miss

albuminuria

< 300mg/24 hours

Albumin dipsticks

Helpful in busy clinic setting

, can detect < 300mg/24 hours

urine albumin

Insensitive for

catergories

of

albuminuria

Albumin

creatinine

ratio

Can classify severity

of urine albumin leakage

Contamination by UTI, menstrual

blood

Increased vascular permeability from -

fever

, sepsis

Orthostatic, exercise, non-steady state

Protein

creatinine

ratio

Insensitive

for

albuminuria

<

300mg/24 hours

Useful for following

up

glomerulonephritis

Microscopy

Can

enable early detection of potentially reversible

glomerulonepritis

Slide8

Why check urine albumin and proteinuria?

Albuminuria

-

a good marker of

glomerular

injury/disease in primary renal and systemic diseases such as diabetes and hypertension

-

reflects damage of

glomerular

filtration barrier with abnormal loss of protein from blood to urine

-

occurs before GFR fall in diabetic

nephropathy

- a marker of cardiovascular disease risk

Glomerular

proteinuria

-

indicates kidney damage even with a preserved GFR

-

contributes to progressive kidney injury (see later discussion)

Early detection is a golden opportunity for preventing ESRD

- treatment of early

albuminuria

with ACEI

and

ARB shown to retard progression of diabetic nephropathy

- treatment of

proteinuria

(

immunosuppressives

for

glomerulonephritis

+ ACEI or ARB) know to retard progression to

end stage kidney disease

Slide9

Approach to urine albumin

EMU = early morning urine

ACR = albumin

creatinine

ratio

PCR = protein

creatinine

ratio

Slide10

Urine analysis

Urine appearance- frothy – proteinuria (nephrotic syndrome)- haematuria – glomerular disease, renal calculi/urinary tract pathology/tumour- coke coloured – acute tubular necrosisUrine microscopy - dymorphic red dlood cells- casts eg red blood cell casts

Slide11

Renal imaging

Renal imaging Abdominal ultrasound scan- appearance – obstruction, polycystic kidneys- size (normal is 9-12cm) - < 9cm in CKD, but enlarged in CKD due to HIVAN, Diabetic nephropathy, amyloidosis and Autosomal dominant polycystic kidney disease- echogenicity (increased in chronic kidney disease)CT scan- can detect obstruction if missed on ultrasound scanRenal vasculature assessments- renal vessel dopplers, nuclear medicine, renal angiography(caution radio iodine induced contrast nephropathy in impaired kidney function)

Dilated calyces

Normal kidney

Echogenic

kidney

Slide12

Kidney biopsy

Indications

Unexplained kidney function impairment with no contra-indications to biopsy

Unexplained

proteinuria

Haematuria

accompanied by

proteinuria

≥500mg/24 hours

Contra-indications

Single kidney

Coagulopathy

Thrombocytopaenia

Uncontrolled hypertension at time of planned biopsy

Sepsis

Inadequate support services

Slide13

Indications for acute dialysis in kidney disease

Hyperkalaemia

> 6mmol/l in

oliguric

patient or refractory to medical Rx

Metabolic acidosis

pH< 7.2 and

re

fractory to treatment of underlying cause

Fluid overload

Uraemic

features

Removal of toxic drugs

Slide14

Chronic kidney

disease (CKD)

Slide15

Chronic kidney disease Definition

Abnormalities of kidney structure or function for > 3 months, with health implications

Classify according to Cause, GFR, and Albuminuria (CGA) In children > 3 months criterion is not required if ≤ 3 month olds < 2 year old use age appropriate values for eGFR vs < 60ml/min/1.73m² Urine albumin ≥ 30mg/24 hours is abnormal

Kidney Intern., supplements 2013

Slide16

Why the < 60ml/min/1.73m² cut off?

Rationale for

GFR

<

60ml/min/1.73m²

cut off

Kidney Disease Outcome Quality Initiative (in the USA) determined that below this cut off there was an increase in the effects of impaired kidney function

:

– hypertension,

anaemia

and derangements in calcium and phosphorus

 

K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. 

 Am J Kidney Dis

2002;39(

suppl

2):S1-S246.

Slide17

Classification

Slide18

What causes chronic kidney disease?

Previous

episode of acute kidney injury or acute kidney disease

- Therefore all patients with a past history of acute kidney injury require follow up of renal function

Intrinsic renal (hereditary, acquired, developmental, part of systemic disease):

-

Glomerular

diseases -

glomerulonephritis

,

glomerulopathies

eg

diabetes, obesity

-

Tubulointerstitial

nephritis – infective, autoimmune, toxins,

neoplasms

eg

myeloma

- Vascular diseases – hypertension,

vasculitis

, atherosclerosis, thrombotic

microangiopathies

, systemic sclerosis, emboli

eg

cholesterol

emboli

-

Hereditary - polycystic

kidney disease

-

Other

congenital diseases (

glomerular

or tubular)

eg

Alport’s

s syndrome

- Chronic infections – HIV, hepatitis B, Hepatitis C, Syphilis, Malaria etc… (can affect all areas of renal parenchyma)

- Drugs & toxins can affect all areas of renal parenchyma, but many cause

tubulo

-interstitial disease herbal, environmental, synthetic, drugs,

Aristolochic

acid containing Chinese herbal remedies

Post renal:

- Chronic

obstruction

Renovascular

- atherosclerotic renal artery

stemosis

,

Takayasu’s

arteritis

etc..

NOTE

:

- Many causes are potentially preventable or modifiable if detected early

Slide19

Other links to chronic kidney disease

In the USA, highest prevalence amongst African Americans - link to Apolipoprotein 1 (APOL1) genetic variants (G1 & G2) ?leading to renal vascular endothelial damage- Trypanosomiasis (cause of sleeping sickness) induces APOL1 expression- In Africa, APOL1 genetic variants protect against trypanosomiasis Low nephron mass – Intra uterine growth retardation, low birth weight, prematurity (Barker –Brenner hypothesis) - Obstetric and Public Health implications

Slide20

From:

Predictors of New-Onset Kidney Disease in a Community-Based Population (Framingham Heart Study)

JAMA. 2004;291(7):844-850. doi:10.1001/jama.291.7.844

Slide21

Chronic kidney disease epidemiology

Chronic kidney disease incidence

- world wide estimate is 8-16%

- little data from Swaziland

Stanifer

et al. The Lancet Global Health 2014

Slide22

What about the pathophysiology? - events leading to progressive renal scarring provide clues to treatment targets in CKD

red

Renal scarring

Reduction in nephron numbers

Glomerular capillary hypertension + hyperfiltration

Increased glomerular permeability tomacromolecules

Increased filtration of plasma proteins including complement, with proteinuria

Excessive tubular reabsorption of filtered proteins

Nuclear signals for NF-KB dependent and independent vasoactive and inflammatory genes & release of their protein products into the interstitium (eg endothelin, cytokines)

Fibroblast proliferation

Tubular cell differentiation

Fibrogenesis and renal scarring

Angiotensin

II mediated

Slide23

Chronic kidney disease symptoms

System

symptom

Symptom

Pathophysiology

Central nervous system

Uraemic

encephalopathy

Uraemic

toxins

Peripheral

nervous system

Peripheral neuropathy

Uraemic

toxins

Dermatology

Pruritis

Leuchonychia

Dry skin

Pallor

Uraemic

toxins

stimulate histamine release with stimulation of

prurigenic

receptors in the skin, and transmission to the thalamus via the spinal cord

Musculoskeletal

Renal

osteodystrophy

Secondary and tertiary hyperparathyroidism

Cardiovascular

Chest pain, heart failure

Intimal

and /or medial vascular calcification /

pericaridial

effusion

Gastrointestinal

Dyspepsia

Hypergastrinaemia

from reduced renal excretion – with

uraemic

gastritis

Genitourinary

Impotence

Oligo-amenorrhoea

Hyperprolactinaemia

,

raised

Leutinizing

Hormone

Immune system

Susceptibility

to infection

Uraemia

causes immune dysfunction

Slide24

Clinical signs of CKD – always look for clues to the underlying cause

CKD 1,2:

>early – asymptomatic, normal acid-base and fluid balance – due to adaptive increase in function in the remaining

nephrons

CKD 3:

> usually asymptomatic, low

erythropoeitin

, low

calcitriol

, secondary hyperparathyroidism

CKD 4:

> pallor (anemia), metabolic acidosis, hypocalcaemia,

hyperphosphataemia

,

hyperkalaemia

CKD 5:

>

uraemic

fetor, fluid overload, hypertension, anorexia, nausea, dyspepsia,

pruritis

, may or may not have

oliguria

Slide25

Chronic kidney disease – clinical features

Yang CS, Robinson-

Bostom L. N Engl J Med 2015;372:1748-1748.

Much can be learnt from examining hands..

- Half and half nails (Lindsay’s

nails

caused by

anaemia

and melanin excess)

- Shortened distal phalanges caused by secondary hyperparathyroidism and renal

osteodystrophy

Slide26

Chronic kidney disease outcome

Go AS et al. Chronic kidney disease and the risks of death, cardiovascular events, and

hospitalisation

. N

Engl

J Med 2004.

Slide27

Expected rate of GFR decline

Slide28

Principles of chronic kidney disease management

CKD 1-3/4

Aim to slow progression by addressing cause and risk factors

Aim to prevent/detect episodes of acute kidney injury quickly – to reduce risk of progression

Aim to treat cardiovascular risks

Immunise

as per patients with chronic illness – high risk of infection: annual influenza vaccination, hepatitis B

immunisation

if negative, 5 yearly pneumococcal vaccine

CKD 4-5

Prepare for renal replacement therapy (peritoneal dialysis,

haemodialysis

, renal transplantation

)

Al l stages

Review drug dosing

Slide29

Selected benefits of early detection of chronic kidney disease

Blood pressure control

Proteinuria

control

Glycaemic

control

Dyslipidaemia

Metabolic acidosis

Smoking

cessation

Weight management, diet, exercise

Renal dose

adjusments

Slide30

Blood pressure control

BP control (hypertension is a cause and a consequence of kidney disease)BP control has clearly been shown to slow the rate of GFR decline - aim < 140/90mmHg if no proteinuria - aim < 130/80mmHg if proteinuriaRationale - BP control limits renal injury - limits glomerular injury – lowers intra glomerular hypertension, reducing proteinuria

JNC 8 Guidelines, JAMA

2014

Maki DD, Ma JZ et al. Long-term effects of antihypertensive agents on

proteinuria

and renal function. Arch Intern Med 1995

Slide31

Proteinuria

Clear demonstration of higher GFR loss rate with increasing degrees of

proteinuria

Strong independent risk factor for CKD

progression

In the African American Study of Kidney Disease (with 1094 patients with hypertensive kidney disease)

-

a doubling in urine protein

creatinine

ratio led to about 0.5

ml/min/1.73m²

/year greater decline in GFR

Slide32

Pathophysiology of proteinuria in chronic kidney disease

> excess filtered protein that includes complement pathway proteins is filtered from the

glomerulus

, into the tubule lumen

Within the proximal tubules:

> these filtered proteins are reabsorbed by the proximal tubule cells

> the complement pathway proteins (including C3, C5b-9), are activated within the proximal tubule cells

> leading to alterations in tubule cytoskeleton, production of reactive oxygen species,

> & production of pro-

inflammtory

mediators via Nuclear Factor kappa B mediated gene transcription

> leading to production of cytokines and other molecules that further augment renal damage – cytokines, growth factors,

vasoactive

substances, Transforming Growth Factor beta

> leading to interstitial fibrosis and extracellular matrix

accummulation

> and

myofibroblast

transformation from macrophages

Within the

interstitium

:

> get focal breaks in the proximal tubule basement membrane

> with leakage of tubular contents, including the reabsorbed filtered proteins, into the renal

interstitium

> leading to protein overload

> and macrophage infiltration

> with production of inflammatory mediators - like

endothelin

1,

monocyte

chemoattractant

protein 1,

osteopontin

, and Transforming Growth Factor beta

> leading to epithelial –

mesenchymal

transformation and

myofibroblast

transformation of macrophages

Slide33

Mechanisms underlying the activation of inflammatory and fibrogenic pathways in proximal tubular epithelial cells by ultrafiltered protein load.

Mauro

Abbate

et al. JASN 2006;17:2974-2984

©2006 by American Society of Nephrology

Slide34

Mechanisms of proteinuria reduction

Addressing the underlying renal cause - appropriate treatment of glomerulonephritis, diabetes, hypertension BP reduction (reduces intraglomerular pressure)- Modification of Diet in Renal Disease study randomised 840 patients with CKD 3 & 4 to low BP target: (<125/75mmHg in ≤ 60y & < 130/80mmHg in > 60y) OR higher BP target of (140/90mmHg in ≤ 60y & 150/95mmHg in > 60y)Found: - Greater GFR decline was shown in the higher BP target group - GFR decline was higher with higher levels of proteinuriaRecommendations - RAAS inhibition with ACEI or ARB (proteinuria reduction shown independent of BP reduction in some studies)- in those intolerant of ACEI or ARB – evidence for the use on non-dihydropiridine calcium channel blockers and the diuretic Indapamide

Saweirs

WWM, Goddard J. What are the best treatments for early chronic kidney disease?

Nephrol

Dial Transplant 2007.

Slide35

Glycaemic control

Glycaemic

control

-

hyperglycaemia

drives

glomerular

injury (see next slide)

Some studies

United Kingdom Prospective Diabetes Study (1997-1997, multicentre, n=5102 newly diagnosed type 2 diabetics)

- intensive

glycaemic

control target HbA1c 7%

vs

conventional

glycaemic

control (at the time) with target HbA1c7.9%

- the intensive arm showed a 25% reduction in micro-vascular end points – including kidney failure

Kumamoto study of type 2 diabetics (Japan, n=110; 55 with no

retinoapthy

& 55 with simple retinopathy)

- randomly assigned to multiple

injection insulin therapy

vs

conventional insulin therapy

- found 28% occurrence and progression of diabetic nephropathy in the conventional therapy group compared to only 6.6% in the multiple injection group

Diabetes Control and Complications Trial in type 1 diabetics

- intensive glucose control reduced the appearance of

microalbuminuria

Slide36

Typical time course stages of diabetic nephropathy

Diabetes duration - years

Stage

Manifestations

Pathogenesis

(ECM=extracellular matrix)

0-3

to 5

I

Renal hypertrophy

Increased

GFR

Hyperglycaemia

RAAS

activation – efferent arteriole vasoconstriction

≥ 3 to 5

II

Basement membrane

thickening

Mesangial

expansion

*

hyperglycaemia

leads to formation of advanced

glycosylation

end products (AGEs)

*AGEs stimulate increased

mesangial

production of ECM

*Have imbalance

between ECM production and degradation

*

Angiotensin

II stimulates ECM production via TGF beta

≥ 7 to 15

III

Stage

I

albuminuria

Hypertension

*Disrupted

glomerular

filtration barrier

*Loss of negative

ly charged

glomerular

basement membrane (GBM)

heparan

sulphate

moieities

≥ 15 to 20

IV

Proteinuria

Hypertension

Decreased

GFR

*Disrupted

GBM as above

*RAAS activation

*

Arteiolosclerosis

of

glomerular

arteries

After

15-25

V

End Stage Renal Disease

Glomerulosclerosis

(nodular

glomerulosclerosis

–

Kimmelstein

Wilson lesions)

Slide37

Targets in glucose control

Slide38

Glycaemia therapy – cautions in CKD

No

metformin

if

eGFR

< 30ml/min/1.73m2 as risk of potentially dangerous lactic

acidosis

Use non-

renally

cleared

sulphonylureas

such

as

Gliclazide

to avoid dangerous

hypoglycaemia

R

emember

glucose may

‘

normalise

’ in advanced diabetic nephropathy because kidneys contribute to

gluconeogenesis

and insulin clearance

Slide39

Example

45 year old patient with type 2 diabetes diagnosed 3 years earlier

On

metformin

eGFR

100ml/min

Urine albumin/

creatinine

ratio is 40mg/g on 2 separate

ocassions

BP 125/80 average

Does he have CKD?

Is he at risk of

progression?

How should he be treated?

Slide40

Treating dyslipidaemia

Hypercholesterolaemia shown in Framingham heart study cohort to be a risk factor for CKD development Data from the Pooled Pravastatin Pooling Project* -(analyzing 3 randomised trials of pravastatin vs placebo; n= 19,700 & 4,491 had CKD 2-3; assessing time to cardiovascular events of myocardial infarction, coronary revascularisation or coronary death) - cardiovascular risk reduction and mortality risk reduction were shown in the CKD patients Benefit is less clear in dialysis requiring CKD as cardiovascular disease is due to more non-atherosclerotic pathology

*

Tonelli

M et al. Effect of

Pravastatin

on

Cardiovscular

Events in People with

Chrinc

Kidney Disease. Circulation 2004.

Slide41

Slide42

Possible mechanisms of slowing of CKD progression by treatment of metabolic acidosis

Surviving

nephrons

in CKD increase ammonia excretion

to

excrete

acid

Ammonia excretion is associated with activation of the complement system and

inflammation, leading ultimately to

tubulo

-interstitial inflammation and fibrosis and worsening CKD

Practical point

Monitor serum

bicarboante

of pre-dialysis CKD patients

Prescribe sodium bicarbonate if <22mmol/l, and aim

≥22mmol/l

Slide43

Smoking and CKD

Review of 9082 US adults in the National Health and Nutrition Examination Survey (NHANES)

II

-

entering the study from 1976-1980, aged 30-74

-followed

through to 1992

Results:

Relative risk of CKD increased in smokers, especially if > 20 cigarettes daily

Smoking causes

proteinuria

and GFR decline (vascular,

glomerular

, tubular injury)

Smoking cessation shown to retard GFR decline

Lifestyle

Factors, Obesity and the Risk of Chronic Kidney Disease

Stengel,

Bénédicte

; Tarver–Carr, Michelle E.;

Powe

, Neil R.;

Eberhardt

, Mark S.;

Brancati

, Frederick L. Epidemiology,

2003

Slide44

Weight loss, exercise, diet

Weight aim - BMI 20-25

- Studies have shown reduction in

proteinuria

with weight reduction

Diet

- low salt aim < 2g/day – high salt increases BP and

proteinuria

& blunts response

t

o

RAAS blockade by Rx

eg

ACEI/ARB

- avoid excess protein >

1.3g/kg/day

as link to

glomerular

hyperfiltration

(but avoid protein energy malnutrition)

Exercise

- some data show benefit independent of weight loss

Slide45

Early kidney disease recognition allows for safe drug dosing

Drugs in kidney disease

- can either cause or worsen

nephrotoxicity

- cause patient morbidity or death from adverse effects of drug accumulation from reduced GFR

Dose according to GFR recommendations in formularies/package

inserts

eg

HAART, TB therapy, some antibiotics

Temporarily hold off potentially

nephrotoxic

drugs in in acutely ill,

hypotensive

patients

Temporarily hold off

antihypertensives

in

hypotensive

, acutely unwell patients

Monitor drug levels in

potentally

nephrotoxic

drugs if possible

Watch for drug interactions

Slide46

Conclusion and Take Home Message

Many potential causes of CKD

Full assessment of kidney function is important

Many potential mechanisms of slowing progression

Slide47