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Chronic Kidney Disease -

General management and standard of care

part 1

Prof Michel Jadoul

Cliniques universitaires Saint-Luc

Université Catholique de Louvain

• Above all, clinical care !

• Pathophysiology is presented only to explain why a

practice is recommended

• The following topics will not be covered:

- diagnosis of the cause of CKD (frequently crucial)

- methods to estimate (or measure) GFR

What should and can be done when managing a CKD patient

Stage Description GFR

(mL/min./1,73m²)

Action

At increased risk >90

(with CKD risk factors)

Screening,

CKD risk reduction

1 Kidney damage

With normal or ↑ GFR

>90

Diagnosis and treatment,

Treatment of comorbid conditions,

Slowing progression,

CVD risk reduction

2 Kidney damage

With mild ↓ GFR

60-89 Estimating progression

3 Moderate ↓ GFR 30-59 Evaluating and treating

complications

4 Severe ↓ GFR 15-29 Preparation for kidney

replacement therapy

5 Kidney failure < 15

(or dialysis)

Replacement (if uremia present)

Management of CKD according to stage (KDOQI 2002)

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KDIGO CKD Guidelines 2012

Section 1: Definition and classification of CKD

Section 2: Definition, identification and prediction of CKD progression

Section 3: Management of progression and complications of CKD

Section 4: Other Complications of CKD: CVD, medication dosing,

patient safety, infections, hospitalizations, and caveats for

investigating complications of CKD

Section 5: Referral to specialists and models of care

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Definition and Classification

1.1. Definition of CKD: CKD is defined as abnormalities of

kidney structure or function for ≥3 months with

implications for health

- this definition specifically excludes simple renal cysts, …..

- If duration < 3 months -> could be CKD or AKI or both

Definition and Classification

Cause GFR Categories

(ml/min/1.73m2)

Albuminuria Categories

(ACR, mg/g)

Diabetes G1 ≥90

A1

<30

Hypertension G2 60-89

Glom Disease G3a 45-59

A2

30-299

Transplant G3b 30-44

Unknown G4 15-29

A3

≥300

etc G5 <15

Tigette OK

N to midly increased

Moderately increased

Severly increased

Staging of CKD (CGA staging)

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Go et al, NEJM 2004

Staging of CKD – GFR and mortality

• The reference point= accurately timed 24h specimen

• Early morning urine preferred

Evaluation of Albuminuria

Relationship between categories of

albuminuria and proteinuria

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Cause GFR Categories

(ml/min/1.73m2)

Albuminuria Categories

(ACR, mg/g)

Diabetes G1 ≥90

A1

<30

Hypertension G2 60-89

Glom Disease G3a 45-59

A2

30-299

Transplant G3b 30-44

Unknown G4 15-29

A3

≥300

etc G5 <15

N to mildly increased

Dipstick neg to trace

Moderately increased

Dipstick trace to +

Severely increased

Dipstick > +

Staging of CKD (CGA staging)

Prognostic value of GFR and albuminuria:

Cohorts and Subjects of CKD Consortium

• Community based populations – With ACR data, 14 studies, n=105,872

– With dipstick data, 10 studies, n=1,239,447

• Populations at increased CVD risk (HTN, diab, CV) – 10 studies, n=266,975

• CKD cohorts – 14 studies, n= 21,688

45 cohorts in total, >1.5 million subjects

Collaborative meta-analysis

Major publications: Lancet, KI, JAMA

Prognostic value of GFR and albuminuria:

Cohorts and Subjects of CKD Consortium

• Community based populations – With ACR data, 14 studies, n=105,872

– With dipstick data, 10 studies, n=1,239,447

• Populations at increased CVD risk (HTN, diab, CV) – 10 studies, n=266,975

• CKD cohorts – 14 studies, n= 21,688

45 cohorts in total, >1.5 million subjects

Collaborative meta-analysis

Major publications: Lancet, KI, JAMA

Matsushita et al, Lancet 2010

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Predictive ability of albuminuria at all categories of GFR:

Meta-analysis from General Population Cohorts -

CKD Prognosis Consortium

Levey, KI 2011

ACR>=300

ACR 30-299

ACR <30

Predictive ability of albuminuria at all categories of GFR:

General Population Cohorts

ACR>=300

ACR 30-299

ACR <30

Levey, KI 2011

Adjusted relative risk of renal and cardiovascular outcomes

for GP cohorts with ACR

Levey et al, Kidney Int 2011

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KDIGO CKD Guidelines 2012

Section 1: Definition and classification of CKD

Section 2: Definition, identification and prediction of CKD progression

Section 3: Management of progression and complications of CKD

Section 4: Other Complications of CKD: CVD, medication dosing,

patient safety, infections, hospitalizations, and caveats for

investigating complications of CKD

Section 5: Referral to specialists and models of care

Definition of CKD progression

• Decline in GFR category (G1-G4)

accompanied by ≥ 25% drop in eGFR from baseline

• Rapid progression defined as sustained decline in

eGFR > 5ml/min/1,73m2/year

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• Cause of CKD

• Level of GFR

• Level of albuminuria

• Age

• Gender

• Elevated BP

• Hyperglycemia

• Dyslipidemia

• Smoking

• Obesity

• History of CVD

• Ongoing exposure to nephrotoxic agents

Predictors of progression of CKD

Anemia, acidosis, bone metabolism, hyperuricemia….

Minimising CKD progression (and CV risk) – BP control

ACR <30mg/g 30-300 mg/g > 300 mg/g

Diabetic ≤ 140/90 mmHg

(1B)

≤ 130/80 mmHg

(2D)

≤ 130/80 mmHg

(2D)

Non

diabetic

≤ 140/90 mmHg

(1B)

≤ 130/80 mmHg

(2D)

≤ 130/80 mmHg

(2D)

Minimising CKD progression (and CV risk) – BP control

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Managing hypertension in CKD patients : a marathon, not a SPRINT !

• SPRINT= CV trail , with a significant proportion of pts with mild-moderate CKD

• SPRINT = NOT A TYPICAL CKD TRIAL

• Standard versus more intensive antiHT therapy in pts with pre-existing CVD or at high CV risk (including the elderly)

• Subjects with advanced CKD or >1g proteinuria were excluded from SPRINT

• Do not generalize ……

Chertow et al JASN 2016; Rocco and Cheung Kidney Int 2016

• KDIGO Blood pressure Guideline currently under revision

Minimising CKD progression

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Lewis et al. NEJM 1993; 329, 1456Lewis et al. NEJM 1993; 329, 1456--14621462

Captopril protects against deterioration in renal function in insulin-

dependent diabetic nephropathy independently of BP control

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Lewis et al. N Lewis et al. N EnglEngl J Med 2001; 345: 851J Med 2001; 345: 851--860860

IrbesartanIrbesartan

AmlodipineAmlodipine

PlaceboPlacebo

The angiotensin-II-receptor blocker irbesartan is effective in protecting against

progression in type 2 diabetes nephropathy, independently of BP control

1715 patients, Target BP ≤ 135/58 mmHg

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Lewis et al. N Lewis et al. N EnglEngl J Med 2001; 345: 851J Med 2001; 345: 851--860860

Mean BP + 3,3 mmHg in placebo vs amlodipine and irbesartan (p=0,001)

ACEi and ARBs are beneficial agents in CKD

• Hemodynamic/antihypertensive actions – ↓ capillary hypertension by ↓ perfusion pressure and efferent

arteriole relaxation

• Anti-inflammatory/anti-fibrotic actions

Turner et al, Kidney Int 2012

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Heeg et al, Kidney Int 1989

The anti-proteinuric effect of lisinopril is dose and time related,

and strongly dependent on dietary sodium restriction

Salt intake 50 and 200 mmol/day

Salt restriction or diuretics :

similar potentiation of ACE-I effect

Buter et al, Nephrol Dial Transplant 1998

low= sodium 50 mmol/d high= sodium 200 mmol/d

Addition of HCT -> ↓ 10% BP ↓ 40% proteinuria

The optimal clinical use of diuretics

• eGFR > 30 : thiazide ( Chlortalidone, « Co…. », « Plus »)

• eGFR < 30 or poor response to thiazide: loop diuretic

(furosemide / bumetanide)

– works for max 6-8h, thus if still poor response , give 2-3 times a day

(8am, 12am and 5-6 pm)

– ! tolerance : cramps (volume –related (not K, Ca, Mg)),

pollakiuria ( prostate…)

– adapt timing of administration to daily activities

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ACE-I, ARB : should we stop them if creatinine rises?

No if creatinine < 3 mg/dl and rising by less than < 30 %No if creatinine < 3 mg/dl and rising by less than < 30 %

Treatment is associated +++ with preservation of GFRTreatment is associated +++ with preservation of GFR

(if creatinine rises +++ (double or triple): look for renal artery (if creatinine rises +++ (double or triple): look for renal artery

stenosis or stenosis or stenosesstenoses))

BakrisBakris et al. Arch et al. Arch IntInt Med 2000; 160: 685Med 2000; 160: 685--693693

Example of a patient with diabetic nephropathy patient already

under Irbesartan: loop diuretic increased progressively

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Hyperkalemia with ACE inhibitors /

angiotensin II receptor antagonist / aliskiren (I)

Is it true hyperkalemia? (to avoid stopping valuable drug because of a laboratory error)

• Time between blood sampling and analysis?

• Hemolysis?

• Confirmed (precautions), severe? (> 5.8 mmol/l)

Dietary ? • Salt substitute

• (Dry) fruit, bananas, chocolate, instant coffee,....

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Correct any acidosis (Vichy 1-2 glasses/d)

ACE inhibitor + angiotensin II receptor or aliskiren:

stop or reduce 1 of the 2

ACE inhibitor (angiotensin II receptor ) + spironolactone:

stop or reduce spironolactone

ACE inhibitor or angiotensin II receptor or aliskiren monotherapy:

dose - add Furosemide

If persistence, add calcium kayexalate 15 g/2 days per os

Awaiting newer K binders (Patiromer, ZS-9)

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Hyperkalemia with ACE inhibitors /

angiotensin II receptor antagonist / aliskiren (I)

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Dual RAAS blockade in CKD ?

Similar results in « Altitude » with Aliskiren + ACEI or A2RB

and in VA trial (Linda Fried et al. ) both in NEJM

Dual RAAS blockade ?

Nephro-protection : reducing proteinuria

with medium to long-term renoprotective effect

(dialysis later ... or never)

Nephro-risk: acute worsening of renal failure

and hyperK if intercurrent disease

(gastroenteritis ++, …)

So block RAAS : YES but usually single agent (ACEi

or ARB) + possibly microdose « cardio »

spironolactone

Association ACE inhibitor + ARB : only if heavy

proteinuria (« glomerular), close, careful

nephrology follow-up in reliable patients

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Rationale:

If BP and proteinuria are well controlled, the slope of CKD

progression will not change much with lower protein intake

In > 65 y old patients, potential for malnutrition !

Protein intake

Glycemic control

Lifestyle measures

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KDIGO CKD Guidelines 2012

Section 1: Definition and classification of CKD

Section 2: Definition, identification and prediction of CKD progression

Section 3: Management of progression and complications of CKD

Section 4: Other Complications of CKD: CVD, medication dosing,

patient safety, infections, hospitalizations, and caveats for

investigating complications of CKD

Section 5: Referral to specialists and models of care

• Strong and independent associations between GFR and albuminuria

categories and risk of CVD in people with CKD

• Cardiovascular risk in CKD is multifactorial

• Cardiovascular disease is more frequent and severe, often not

recognised and undertreated in patients with CKD

• Patients with CKD should be considered amongst the highest risk

groups for CVD

• To prevent progression of CKD is to prevent CVD

Classical CV risk factors

Not modifiable Modifiable but no proven benefit

Modifiable with clinical benefit

Older age Uric acid Smoking

Male gender Homocysteine Obesity

Ethnicity Hypertension

Lp (a) Diabetes

HDL cholesterol LDL cholesterol

Physical activity

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Lipid control and antiplatelet therapy

• No specific lipid targets are established in CKD patients

-> treat in accordance with guidelines for other high-

risk populations

If high-risk, prescribe a statin whatever the LDL

cholesterol

• Antiplatelet therapy should be offered to high risk

patients unless bleeding risk outweighs CV benefits.

Gansevoort et al, Lancet 2013

• Even if cause of CKD not treatable, much can and should

be done for any CKD patient

• Treat BP to target and aggressively substantial

albuminuria; both interventions delay CKD progression

• Underuse of salt restriction/diuretics !!

• Manage aggressively classical CV risk factors

Chronic Kidney Disease -

General management and standard of care

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CKD general management and standard of care (part 2)

Prof. Michel Jadoul Cliniques Universitaires Saint-Luc Université Catholique de Louvain

Brussels, Belgium

Stage Description GFR (mL/min./1,73m²)

Action

At increased risk >90 (with CKD risk factors)

Screening, CKD risk reduction

1 Kidney damage

With normal or ↑ GFR

>90

Diagnosis and treatment, Treatment of comorbid conditions,

Slowing progression, CVD risk reduction

2 Kidney damage

With mild ↓ GFR

60-89 Estimating progression

3 Moderate ↓ GFR 30-59 Evaluating and treating complications

4 Severe ↓ GFR 15-29 Preparation for kidney replacement therapy

5 Kidney failure < 15 (or dialysis)

Replacement (if uremia present)

KDOQI 2002 Guideline for CKD

Not covered

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Thus • no treatment of asymptomatic hyperuricemia • after 1 gout attack , allopurinol proposed to those at risk of relapse (= vast majority:substantial CKD/ diuretics/…) •Febuxostat more potent than allopurinol (but more costly, and off-label use for e GFR <30) •AVOID AZA with both allopurinol and febuxostat •Attacks treated with – very low-dosage of colchicine dosage in CKD ! drug interactions with statins and other CYP3A4 inhibitors – short course of corticosteroids (32 mg methylpred for 5 days) (– NSAIDS alternating with low-dose colchicine)

61 y old man, IgA GN, 24 y TP, then recently started on HD Pericardial effusion : daily HD, little/no heparin Colchicine 0.5 mg then 1mg/day Medrol 2mg/d, CsA 200mg/d, Rosuvastatin 10mg / d

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Refractory shock … and death

Colchicine largely eliminated by the liver, somewhat by kidney Metabolism inhibited by some CCB, CNI, antifungals, macrolides , some statins ….. Here CsA + rosuvastatin + colchicine for some weeks = deadly combination Thus use lowest possible colchicine dosage, for very short period and beware of drug interactions

Drug dosage in CKDDrug dosage in CKD

•• StartingStarting dosagedosage

** aimaim: : therapeutictherapeutic bloodblood levellevel : ex. : ex. vancomycinvancomycin

** functionfunction of distribution volume of distribution volume (V , or (V , or weightweight and and drugdrug distribution distribution bloodblood/tissues)/tissues)

** thusthus normal in CKD (or normal in CKD (or eveneven increasedincreased if if oedemaoedema +++)+++)

•• Maintenance dosage Maintenance dosage

** eliminatedeliminated by by liverliver : : littlelittle or no change or no change ((metabolitesmetabolites !) !)

** eliminatedeliminated by by kidneykidney : : increaseincrease intervalinterval or or reducereduce dosagedosage

Drug dosage in CKD (II)Drug dosage in CKD (II)

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Maintenance dosage unchanged in CKD

•• CalciumCalcium--channelchannel blockersblockers , , metoprololmetoprolol

•• Nitrates Nitrates

•• Standard (Standard (unfractionatedunfractionated) ) heparinheparin, AVK, AVK

•• ClonidineClonidine, , guanfacineguanfacine, , moxonidinemoxonidine

•• DoxycyclineDoxycycline, , oxacillineoxacilline, , rifampicinrifampicin

•• StatinsStatins

•• PPIPPI

•• CorticosteroidsCorticosteroids , all«, all« steroidssteroids » » (OP,…)(OP,…)

•• cyclosporine, cyclosporine, tacrolimustacrolimus

Maintenance dosage reduced in CKD

•• SotatolSotatol :class III :class III effecteffect, QT , QT prologationprologation, , suddensudden deathdeath!!

•• LMW LMW heparinsheparins

•• ColchicineColchicine

•• Allopurinol Allopurinol

•• MethotrexateMethotrexate……

•• Lithium …Lithium …

•• Morphine Morphine derivativesderivatives ( ( codeinecodeine, morphine, , morphine, fentanylfentanyl,….),….)

•• DigoxineDigoxine

•• GanciclovirGanciclovir, acyclovir ,…, acyclovir ,…

•• ManyMany othersothers ………………….………………….

•• NovelNovel oral anticoagulants (oral anticoagulants (avoidavoid somesome, , nextnext slideslide))

In case of In case of doubtdoubt, check !!, check !!

Pradaxa Eliquis Xarelto

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Acidosis = anti-anabolic Progression of CKD : some evidence that acidosis may accelerate progression

de Brito-Ashurst I, Varagunam M, Raftery MJ, Yaqoob MM. J Am Soc Nephrol. 2009

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Mrs V - 82 y old type 2 Diabetes II - Hypertension Admitted in emergency room on 26/09/2004 : vomiting- unwell Home treatment: Zestril 20 mg/j, Aldactazine 1/j, Glucophage 850 mg 2/j, Selozok 100 mg/j, Glurenorm 3/j

Clinically : BP 120/80, dehydrated

Bio: pH 7.06

Bicarbonate: 6, Lactate: 7.7 (nl < 1.3)

K: 8.4

urée: 164

créat.: 8.4

Hb: 10.7

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severe AKI on mild CKD

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WARN the PATIENTS to WARN the PATIENTS to

1) stop drug(s)1) stop drug(s)

22) request clinical ) request clinical and biochemical check! (and biochemical check! (créatcréat, K, drug level , …), K, drug level , …)

Drugs eliminated by kidneyDrugs eliminated by kidney + + eGFReGFR< 45ml/’ + fever ++ < 45ml/’ + fever ++

or or diarrheadiarrhea ++++

Narrow therapeutic indexNarrow therapeutic index or vomiting. or vomiting. ++++

-- biguanidesbiguanides

-- spironolactonespironolactone

-- lithiumlithium

-- methotrexatemethotrexate

-- digoxinedigoxine

-- ACEI/ ARB + diureticsACEI/ ARB + diuretics

Precautions under some drugs !

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« End-stage » or « terminal » renal disease

• Does not equal to (quasi)- death sentence

• Human species is adaptative

• Anxiety will usually be reduced by adequate information, rather than increased

• Any patient with advanced CKD knows about a single patient, very sick, who died rapidly after dialysis start

ESRD treatment Modalities

• Transplantation, including preemptive , both living and deceased -donor

• Haemodialysis – In-centre – Self care satellite (1984) – Home HD (1970) , with partner or solo or with

nurse ( partly reimbursed 2003) – Satellite non-self care (2006, 2012)

• PD (1978) – CAPD – APD

• Conservative treatment

PDEP Programme (1)

• Nephrologist initiates discussion and briefly (30 minutes) explains the various RRT modalities

• Suggests appointment with self-care team

• Indicates which modalities are “reasonable” in the particular patient (written form)

e.g. Crohn’s disease and extensive abdominal surgery : no PD

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PDEP Programme (2)

• Information provided by nurses in charge of self-care dialysis (median >20 years in unit)

• Individual (preferably with family)

• In-house Video with further details on modalities and videos of patients on all modalities

• Questions/answers : job, timing, eating, sleeping, holidays, travelling, sexual,...

PDEP Programme (3)

• Next outpatient nephrology clinic : further discussion with nephrologist

• Brochures

• Contact with experienced patients

• Sometimes video and Q/A second time with team

( repeating = important)

• Should be started early enough (slope of eGFR), human brain complex , and opinions may change

• Preference(s) of patient crucial ! (except gross CI)

• Adherence to treatment better if “self- choice “

Experience 1994-2000

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CLINIQUES UNIVERSITAIRES SAINT-LUC 104

Khosla S and Melton L. N Engl J Med 2007;356:2293-2300

Lifestyle Measures Recommended for Patients with Osteopenia

Discussion (I)Discussion (I)

•• Patient Population :Patient Population :

-- relatively few patients with very low sociorelatively few patients with very low socio--economic status economic status

-- only 10 % diabetics at that time , now much only 10 % diabetics at that time , now much more , but strategy unchanged more , but strategy unchanged

•• Large sized nephrology unit, thus all modalities Large sized nephrology unit, thus all modalities availableavailable

CLINIQUES UNIVERSITAIRES SAINT-LUC 105

Khosla S and Melton L. N Engl J Med 2007;356:2293-2300

Lifestyle Measures Recommended for Patients with Osteopenia

Discussion (II)Discussion (II)

•• EnthousiasmEnthousiasm for selffor self--care !!care !!

•• Patients may be Patients may be transferedtransfered back from satellite or back from satellite or

home or PD to inhome or PD to in--centre HDcentre HD

•• inin--centre HD : not a second choice, just a choicecentre HD : not a second choice, just a choice

•• OpenOpen--minded, transparent, honest minded, transparent, honest

•• Goal : best interest of patient Goal : best interest of patient

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CLINIQUES UNIVERSITAIRES SAINT-LUC 106

Khosla S and Melton L. N Engl J Med 2007;356:2293-2300

Lifestyle Measures Recommended for Patients with Osteopenia

A team workA team work

Professor Eric Goffin

Mr Tony Goovaerts

Mr Philippe Cougnet

Whole nephrology unit

average 12

average 9.8

Cockroft-Gault !

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Summary

• Stage 3-5 CKD : many potential complications • Some (too) well known : anemia, CKD-MBD • Many less well known : drug accumulation,

acidosis,…… are avoidable/manageable • Planning RRT with fully informed consent - selfcare (HD including home, PD) - preemptive TP - in-center HD - conservative management • Planning RRT well in advance does not equal to early

RRT start