CKD – The long term view

Catherine Byrne

Adult Consultant Nephrologist

Nottingham University Hospitals

September 2019

Introduction

• What is CKD?

• Outcomes

• Delaying Progression

• Monitoring

• Pregnancy and fertility

What is CKD?

• 1 in 10 people in UK have chronic kidney disease (CKD)

• Total cost CKD in England 2009/10 £1.44-1.45 billion

• Rising incidence and prevalence worldwide

• Adult secondary care sees tip of the iceberg

• Most patients with CKD don’t progress to end stage (2%)

• Progression can be delayed by medication and

behavioural interventions

Classification of CKD

Stage eGFR

(ml/min) Description

G1 90+ Normal or increased GFR, with other evidence of kidney damage

G2 60 – 89 Slight decrease in GFR,

with other evidence of kidney damage

G3A 45 - 59 Moderate decrease in GFR with or without other evidence of kidney damage G3B 30 – 44

G4 15 – 29 Severe decrease in GFR

G5 < 15 Established renal failure

Use cystatin C to distinguish CKD from normal if eGFR 45-59mls/min & no proteinuria

Rising currency of Cystatin C

• A low molecular weight cysteine protease inhibitor- produced by all

nucleated cells

– Filtered at the glomerulus and not reabsorbed

– Serum concentration mainly determined by GFR

– Inflammation, thyroid disease, and steroids may affect levels

– Less dependent on race and body mass

• Potential uses:

– Confirming stage 3a CKD (eGFR 45-59 ml/min)

• NICE: Consider using Cystatin C to confirm

CKD in patients with eGFR 45-59 and ACR <3mg/mmol

• Assessing for CKD in malnourished patients

• cost implications: approx £20

Proteinuria/Albuminuria

Albuminuria predicts

worse outcomes

Blue – normal ACR

Green – microalbuminuria

Red - macroalbuminuria

Note log scale on Y axis for Hazard Ratio

Adapted from Levey et al, 2010, Kidney International

Patients with CKD are more likely to die than require dialysis:

27,998 CKD patients followed for 5 years:

Stage GFR (ml/min) RRT Death

2 60-89 1.1% 19.5%

3 30-59 1.3% 24.3%

4 15-29 19.9% 45.7%

Keith DS, AIM 2004;164:659-663

What really happens to adult

patients with CKD?

CKD is an independent and major risk factor for cardiovascular disease

15% increase in CV mortality for every 5ml/min reduction in CrCl

Cardiovascular Mortality in ESRD

0.01

100

10

1

0.1

Annual mortality (%)

25–34 45–54 65–74 85 35–44 55–64 75–84

Male

Female

Black

White

Dialysis

General population

Age (years)

Childhood Kidney Disease

Calderon-Margalit R et al. N Engl J Med 2018;378:428-438

Outcome Variables and Hazard Ratios for ESRD in Adulthood, According to Childhood Kidney Disease Category at Recruitment.

Calderon-Margalit R et al. N Engl J Med 2018;378:428-438

Life Tables of the Cumulative Incidence of ESRD

among Study Participants During the Follow-up Period.

Calderon-Margalit R et al. N Engl J Med 2018;378:428-438

How can we delay

progression?

• Potentially modifiable risks:-

Lifestyle

• Stop smoking

• Obesity – reduce to normal BMI

• Take regular exercise

Treat diabetes – tight control

Treat high blood pressure

ACE inhibitors (ARBs) for albuminuria

Lipid lowering

Interventions to prevent or

delay progression

Nephrology Dialysis Transplantation, Volume 32, Issue 3, March 2017, Pages 475–487, https://doi.org/10.1093/ndt/gfw452

Estimates of the RR of developing CKD for (A) ever-smokers, (B) former smokers and

(C) current smokers.

31% increase in RR of rise in creatinine by

≥27µmol/L during 3 years for every 5

cigarettes smoked/day

If DM doubles rate of progression to ERF

Global Disability-Adjusted Life-Years and Deaths Associated with a High Body-Mass Index (1990–2015).

The GBD 2015 Obesity Collaborators. N Engl J Med ;377:13-27

Hypertension is common

GF

R

(mL

/min

/y)

-14

-12

-10

-8

-6

-4

-2

0 95 98 101 104 107 110 113 116 119

MAP (mm Hg)

r =0.69; P<0.05

Untreated

hypertension

140/90 130/85

The importance of BP control

Management: delaying

progression - BP control

The importance of ACE inhibition

Ramipril

Placebo

Pharmacotherapy

ACE inhibitors/ARBs* should be offered to the following:

ACE inhibitors are first line treatment for all

Change to ARB only if ACE not tolerated

Diabetic Non-

diabetic

Non-

diabetic

ACR (mg/mmol) >3 >30 >70

PCR (mg/mmol) >50 >100

Need to confirm CKD No Yes Yes

Need to confirm high BP No Yes No

Monitoring

Progressive CKD

CKD progression is decline of: – >5ml/min/1.73m2 in 1 year

– >10ml/min/1.73m2 in 5 years

Risk Factors:

CVD Proteinuria

Smoking AKI

HT DM

Secondary care focuses on those likely to need RRT

Integration of GFR and albuminuria

when evaluating risk

25

No CKD (88%)

Mild risk (9.2%)

Moderate risk

(2%)

High risk (<1%)

Levey, Eckardt, Gansevoort et al, KI 2011

Based on 4 meta-analyses of

45 cohorts with 1.5million

individuals, studying 5

endpoints

Guide to frequency of monitoring by

GFR and albuminuria category

NICE referral criteria

Stage 5 Urgent referral unless …

Stage 4 Refer unless …

Irrespective sustained ↓GFR ≥ 25% & change GFR category

of GFR sustained ↓GFR of ≥15mls/min within 12 months

urinary ACR ≥30mg/mmol & haematuria

urinary ACR >70 mg/mmol (unless due to DM)

suspected multisystem disease

BP > 150/90 on 4 agents

rare or genetic cause of CKD

suspected renal artery stenosis

Pregnancy and CKD

1. Fertility issues in CKD

2. Brief overview of pregnancy

and kidney disease

Fertility issues in CKD

National Statistics Online. Conception statistics 2008.

http://www.statistics.gov.uk/downloads/theme_health/conceptions2008/conceptions08.pdf

Brown JH, Maxwell AP, McGeown MG. Irish J Med. 2001

Barua M, Hladunewich M, Keunun J et al. Clin J Am Soc Nephrol. 2008;3:392/396

Okundaye IB, Abrinko P, Hou S. Am J Kidney Dis 1998; 31(5):974-981

Endocrine

Diminished

ovarian

reserve?

Medication

effects

Diminished libido,

fatigue and

psychosocial

factors

Contraception

• Safe & effective contraception offered to all females of

reproductive age with CKD

• RA guidance recommends POP, progesterone

subdermal implant (Nexplanon) & progesterone intra-

uterine system (Mirena) are safe & effective

• Study of 76 women with CKD: 50% sexually active, only

36% using contraception & 13% d/w nephrologist *

• Unintended pregnancy associated with increased risk of

obstetric complications

*Holly JL et al AJKD 97;29:685-90

Pre-pregnancy planning

• If have CKD refer for pre-pregnancy counselling

• If known or suspected inheritable renal disease

offer genetic counselling/referral

• Ensure on folic acid

• Start low dose aspirin once 12/40 pregnant

• If SLE or vasculitis wait 6 months with quiescent

disease

• CKD 4 or 5 need pre-dialysis education as 1 in 3

risk will need dialysis within 1 year of pregnancy*

*Piccoli GB JASN 2015;26:2011-22

Hall M. Pregnancy in Women with CKD: A Success Story. Am J Kidney Dis. 2016 Oct;68(4):633-9

Pregnancy outcomes with kidney disease over time

Will pregnancy make my

kidneys worse?

Probably, if you have CKD 4 or 5

Probably, if you have CKD 3b and

proteinuria

Probably not, if you have CKD 1-3a

0

10

20

30

40

50

60

70

80

90

100

25% decline in

renal function in

pregnancy

Persistent 25%

decline at 6/12

Persistent 25%

decline at 1 year

RRT at 1 year

%

CKD 3a

CKD 3b

CKD 4-5

Data included in Wiles K, Webster P, Bennett-Richards K et al. Obstetric and renal outcomes of pregnant women with chronic kidney disease (CKD) stages 3-5. (Submitted)

69 women

Prospective study 2004-2011

Preconception eGFR <60ml/min

Will my CKD harm my baby?

Your baby is likely to be born

earlier and smaller than normal.

Particularly if you have more

severe kidney disease or high

blood pressure

507 pregnancies

Prospective study

2000-2013

Piccoli GB, Cabiddu G, Attini R et al. J Am Soc Nephrol 2015;26:2011

7/507 (1.3%) fetal deaths

Maternal indication

Fetal indication

Combined maternal and

fetal indication

Spontaneous preterm labour

Reasons for preterm delivery

92.5% of preterm

deliveries iatrogenic

Piccoli GB, Attini R et al. Clin J Am Soc Nephrol 2010;5(5):844

Antenatal care in CKD

Monitoring and interventions

Medicines

management

Blood pressure

control

Pre-eclampsia

prophylaxis Thrombo-

prophylaxis

Bacteriuria

treatment

Timing of delivery

Preconception

counselling

Medicines

management

Blood pressure

control

Pre-eclampsia

prophylaxis

Thrombo-

prophylaxis

Bacteriuria

treatment

Antenatal care in CKD

In pregnant women with CKD and treated hypertension, the target

blood pressure should be 120-139 / 70-85 mmHg.

Low dose acetylsalicylic acid (aspirin 75mg/day) is

recommended for the prevention of pre-eclampsia

at women at high risk of developing the condition.

Women with nephrotic syndrome should have thromboprophylaxis in

pregnancy and for 6 weeks postpartum

Women with substantial proteinuria (ACR>70, PCR>100) should be risk-

assessed for VTE and considered for thrombo- prophylaxis in pregnancy

and for 6 weeks postpartum

RDG Consensus 2017

RDG Consensus 2017

Treat asymptomatic bacteriuria during pregnancy

Consider prophylactic antibiotics for women (a) with recurrent episodes of

bacteriuria (b) who are immunosuppressed (c) abnormal renal tract anatomy

RDG Consensus 2017

Summary

• Previous kidney disease in childhood, even with normal

renal function, confers increased risk of ERF in

adulthood

• Monitoring for life is essential in such patients but can be

undertaken in primary care for selected groups.

• Active management to reduce risk factors can delay

disease progression

• Ensure all females of child bearing age are offered

contraception

• Pregnancy can be high risk but can be safely managed

in a specialist MDT

Further information

www.nice.org.uk/cg182 for CKD guideline

www.renal.org

KDIGO Clinical Practice Guideline for the Evaluation and

Management of CKD, 2012

https://renal.org/wp-content/uploads/2019/09/FINAL-Pregnancy-Guideline-September-2019.pdf

via Choose and Book for local CKD guidelines

catherine.byrne@nuh.nhs.uk

Endocrine Fertility issues in CKD