CAPSULE INDIVIDUALISATION THERAPEUTIQUE

NEW APPROACHES IN NEPHROLOGY

Prof Belén Ponte, PhD & Msc Epidemiology

Médecin adjointe agrégée, CC
Service of Nephrology
University Hospital of Geneva
 PLAN

Epidemiology Chronic Kidney Disease (CKD)

Renal function definition

CKD definition

Glomerular Filtration rate (GFR): How to measure it ?

CKD and drugs?

Take home messages

Webster AC. Lancet 2016
 Webster AC. Lancet 2016

CKD MORTALITY

14th mortality cause → 12.2 deaths per 100’000 persons-year

 IRC “AWARENESS” Provided by AstraZeneca

Fewer than half of all CKD cases are diagnosed…a

Prevalence of diagnosed CKD cases in CKD patients in Prevalence of diagnosed and undiagnosed CKD cases in CKD
CURE-CKD registry1,b,c stage 3 patients2,3

89.2
Ravera et al.,
(2011)
10.8
Diagnosed
40.7% Undiagnosed
Not diagnosed
85.9 Diagnosed
59.3%
Ryan et al.,
(2007)
14.1

0 20 40 60 80 100
Data collected:
January 2006 – December 2017 Patients (%)

…with over 85% of CKD stage 3 cases still undiagnosed

aExcludingend-stage kidney disease; bEHR-based registry jointly curated and sponsored by PSJH and UCLA using Epic EHRs (Epic Systems); cDiagnosed CKD cases defined as those calculated
by the CKD-epidemiology equation from the mean of at least two serum creatinine measurements ≥90 days apart
CKD, chronic kidney disease; EHR, electronic health record; PSJH, Providence St. Joseph Health; UCLA, University of California, Los Angeles
1. Tuttle KR, et al. JAMA 2019;2:e1918169; 2. Ryan TP, et al. Am J Med 2007;120:981–986; 3. Ravera M, et al. Am J Kidney Dis 2011;57:71–77
 CKD “AWARENESS” in the general population
77% of the general public know little to nothing about CKDa
Condition knowledge
(general public)b Top3
How much, if anything, do you know about each of the following conditions? Please select one answer per condition. (net)

Heart failure 3% 17% 43% 29% 8% 80%

Cancer 3% 7% 37% 39% 14% 90%

Respiratory diseases (e.g. asthma, COPD) 3% 17% 42% 28% 9% 79%

Diabetes 2% 10% 37% 35% 15% 87%

Chronic kidney disease 5% 4% 36% 37% 14% 5%

56%

Alzheimer's disease 3% 14% 43% 30% 9%

82%

Don't know Never heard of Hardly anything Only a little A fair amount A lot
aParticipants that answered ‘don’t know’ not included; bSample size (general public): 18,243
Percentages under 3% have been removed from graph
CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease
 RENAL FUNCTION(S)

✓ Glomerular Filtration
✓ Excretion / absorption : nitrogenous products, Na, K, Ca, Ph, Mg, H20

✓ Homeostasis regulation
✓ Acid base equilibrium

✓ Blood Pressure contrôle

✓Renin-angiotensin-aldosteron axis
✓Erythropoietin secretion
✓Vitamin D hydroxylation
 GLOMERULAR FILTRATION RATE (GFR)

= Volume of plasma that is filtered by the glomeruli per unit of time.

Can be measured by the clearance of a substance that is only filtered,
neither reabsorbed nor secreted.

GFR = ClearanceX = (UX * urine flow rate/min) / PlasmaX

20% of the plasma flow is filtred across glomerular capillaries

Normal: 120ml/min in men and 100ml/min in women

GLOMERULAR FILTRATION BARRIER

→ Drugs highly protein-bounded are not filtrated

→ Can be secreted through proximal transporters
Tryggvason K. NEJM 2006
 DEBIT SANGUIN RENAL

Débit cardiaque (Dc) total: 5-6L/min

Débit sanguin rénal (RBF): 20% Dc

→ environ 1L/min
20%
Débit plasmatique rénal (RPF): 600ml/min
RPF = (1-Ht) x RBF si Ht 40%

80%
20%
 DEBIT SANGUIN RENAL

Débit cardiaque (Dc) total: 5-6L/min

20%

80%
20%
Débit filtration glomérulaire (GFR): 20% RPF
→ environ 120ml/min → 180L/j
Modulation filtration glomérulaire
Le but est de maintenir un taux de filtration glomérulaire constant:
Contrôle du diamètre des a. afférentes et efférentes est essentiel
 autoregulation

Drugs can affect GFR and autoregulation

Diabète et Filtration: iSGLT2
X 8.8 → mg or g/g

Ruggenenti. BMJ 1998

 URINARY
However, urine TESTING
CKD testing is underutilized
Electronic health records from 39 US healthcare Percentage of patients with urine CKD testing
organizations1 by comorbidities2
976,299 patients with eGFR <60 mL/min/1.73 m2 90
80

80.7% 70

Patients (%)
60
received no UACR testing over 3 years None
50 eGFR
40 UACR
30 Both

Primary care setting2 20

270,170 patients at risk of CKD due to DM, HTN, or both 10
0
Although 94% of patients were tested for eGFR DM + HTN DM only HTN only

Only 56% of patients were tested for UACR UACR testing is lower in patients with HTN compared with
those with diabetes

CKD, chronic kidney disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HTN, hypertension; UACR, urine albumin:creatinine ratio
1. Naranja FS, et al. Kidney360 2021. doi: 10.34067/KID.0005592020 [Epub ahead of print]; 2. Bansal S, et al. Kidney360 2020;1:904–915
 GLOBAL AND CV MORTALITY

ACR <30mg/g ACR 30-299mg/g ACR>300mg/g

ACR: albumine urine /creatinine urine.
Matsushita K et al. Lancet 2010
CKD STRATIFICATION

Levey et al. Lancet 2010

KDIGO 2012.
 PROGRESSION RISK FACTORS Provided by AstraZeneca

Obesity Smoking Age Sex Race/ethnicity

Level of Level of
albuminuria Progression of chronic kidney disease eGFR

Hypertension Diabetes Cause of CKD Dyslipidemia CV disease

Persons with hypertension, diabetes, or CVD should be screened for CKD2

CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate
1. Kidney Disease Improving Global Outcomes. Kidney Int Suppl 2013;3:1–150; 2. Shiplak MG, et al. Kidney Int 2020. doi: 10.1016/j.kint.2020.10.012
https://kidneyfailurerisk.com/

KFRE: Kidney Failure Risk Equation

Risk of progression to kidney failure

requiring dialysis or transplant over 2 and 5 years
 GFR: HOW TO MEASURE IT?

Ideal marker X GFR X = Clearance X

Ideal marker goes completely blood to → urine :

✓Freely filtered
✓Neither secreted nor reabsorbed by tubules
✓Not metabolised
✓Renal elimination only
✓Constant production (if endogenous)

Ideal endogenous marker: DOES NOT EXIST Traynor J. BMJ 2006

Glassock. KI 2009
MESURE du GFR (mGFR)

CV= 7%

CV= 5-15%
Inulin clearance = gold standard mesure for GFR
GFR:
Inuline GOLD
(polymer STANDARD
de fructose) MEASURE
= marqueur exogène
Mais:
- perfusion continue + collection urinaire pendant env 4h
- sondage vésical +- nécessaire
- coût et temps!

Traynor J. BMJ 2006

Glassock. KI 2009
 GFR: NUCLEAR MEDICINE

Exogenous markers injected:

✓ Radioactive contrast agents:
Iothalamate, 51Cr-EDTA, 51Tc-DPTA
✓ Non-radioactive: Iohexol
Confirmatory tests but still biological variations (5-12%)
CREATININE = “Ideal” marker ?
 Age - gender - ethnicity

1. Extra-renal factors

Liver metabolism

2. Renal factors

« Functional reserve »

Steady state !

Star. KI 1998
RELATION CREATININE - mGFR

Creatinine ↑ when GFR ↓ by >50%:

Exponential relation
 CREATININE measure?

✓ Jaffe: colorimetric reaction with picrate (yellow-orange) that can be

quantified → interaction with bilirubin, drugs, pseudochromogens
(acetoacetate, pyruvate, keto-acids..)

✓ Jaffe kinetic, compensated

✓ Enzymatic: better analytical precision ++ if creat low (pediatry,

hyperfiltration, bilirubin…)

✓ Calibration assays to standardised measures: IDMS (Isotope

Dilution mass spectrometry) traceable methods
Delanaye P. Nepron Clinical Practice 2017
EQUATIONS ESTIMATING GFR

Bourquin. Nephroblog.
CKD-EPI 2021
 Nephron 1976; 16:31-41
www.kidney.org
Stevens. Clin Pharmacol Ther 2009

COCKROFT-GAULT - CG

Developed by a 3rd year medical student in 1976

N= 249 males, compared to 24h urinary creatinine clearance

Ccr= [(140-age) (Weight in kg)] / [72* Scr (mg/100ml)] ml/min

“ The CG equation is inacurate in the era of standardized creatinine

assays and is no longer recommended for use”

Many drugs developed using this equation for pharmacokinetic studies

but risk of overdosing because of renal function overestimation
 CKD-EPIdemiology
Development from 10 pooled studies
N=8254 for development ; n=3896 for validation

eGFR= 141 * min(Scr/k, 1)α * max(Scr/k, 1)-1.209 * 0.003Age

* 1.018 (women) * 1.159 (african)

K: 0.7 women; 0.9 men

α: -0.329 women; -0.411 men

✓Better than MDRD for mGFR ≥ 60ml/min

✓ Less biased for age, gender, ethnicity, diabetes and transplant
✓ Less biased for obeses →Diminue prévalence CKD par rapport à MDRD

Caveat: developed with IDMS standardised creatinine

Stevens. AJKD2010
Levey AS. AJKD 2010
 DISTRIBUTION eGFR: MDRD vs CKD-EPI

MDRD CKD-EPI

General Lausanne Population (CoLaus study )

N= 5921 Ponte et al. NDT 2013
PREVALENCE DEPENDS ON THE MEASURE!

eGFR< 60ml/min/1.73m2:
MDRD 8.7%
CKD-EPI 6.3%

Matsushita K et al. JAMA 2012

 CYSTATINE C

Protéine 13kD produced by all nuclear cells at constant rate

Extracellulaire inhibitor of cystéine protease

Freely filtered, non secreted, completely reabsorbed and metabolised by tubules

Herget-Rosenthal. Kint 2004

Knight E. Kint 2004
Eriksen BO. KI 2010
Glassock. Nat rev 2017
 CYSTATINE C: Equations

Better mortality prediction

Better ESRD prediction

Peralta C. JAMA 2011

Copyrights apply
= European Kidney Function
Consortium
 Levey As. Nat rev Nephrology 2020; vol 16.p 51

EQUATIONS eGFR: Performance par rapport à mGFR

 EQUATIONS: ACCURACY?

Accuracy= Absence de biais + précision

eGFR dans les 30% de mGFR= satisfaisant

Guidelines: 90% participants de la population de validation
doit avoir un eGFR dans les 30% du mGFR
→ P30 ≥90% ou 1-P30

Inker L. NEJM 2012

http://ckdepi.org/equations/drug-dosing/
RENAL FUNCTION DECLINE WITH AGE

After >70 yo, 50% eGFR < 60ml/min/1.73m2

1/3 will not have decline in eGFR?

Ponte B. Nephrol Dial Transpl 2013

 Age < 40 ans → CKD <75ml/min
Age 40-60 ans → CKD <60ml/min
Age > 65 ans → CKD < 45ml/min

<75ml/min <45ml/min

* *

<60ml/min <45ml/min
* *
60% increase of CKD incidence using fixed threshold, mainly in older >65 with eGFR 45-59 & low ACR
10% age-CKD not identified by fixed threshold
OTHER BIOMARKERS?

Zhang WR. Ann Rev Physiol 2019

BIOMARKERS: Kidney is an Heterogeneous diseases?

Zhang WR. Ann Rev Physiol 2019

Zhang WR. Ann Rev Physiol 2019
 UROMODULIN: new marker?

Most abundant protein in urine. Secreted in TAL segment Devuyst. Kint 2015
Scherberich JE. NDT 2018
OMIC APPROACH
METABOLOMIC APPROACH
From Prof Rudaz

Two major technologies are well-established today: NMR and MS

A

CTRL CKD3b/4 CKD5 CTRL CKD3b/4 CKD5 CTRL CKD3b/4 CKD5 CTRL CKD3b/4 CKD5 CTRL CKD3b/4 CKD5

CTRL CKD3b/4 CKD5 CTRL CKD3b/4 CKD5 CTRL CKD3b/4 CKD5 CTRL CKD3b/4 CKD5 CTRL CKD3b/4 CKD5

CTRL CKD3b/4 CKD5 CTRL CKD3b/4 CKD5 CTRL CKD3b/4 CKD5 CTRL CKD3b/4 CKD5 CTRL CKD3b/4 CKD5
 Mahmoud. Curr Op HypertNephol 2016

GFR: MAGNETIC RESONANCE?

 Dynamic-contrast-enhanced MRI (DCE-MRI)

Ebrahimi B. CJASN 2014

Perfusion and renal filtration measured Grenier N. Nat rev nephrol 2016
 Blood-oxygen-level IRM (BOLD-irm)

Renal oxygenation measured Ebrahimi B. CJASN 2014

Grenier N. Nat rev nephrol 2016
Nephroprotection?
2016

ACE > ARB

Landmark trials in diabetic nephropathy

Sawaf D. JDC 2022

 Inhibiteurs SGLT2

Giorgino et al. Cardiovasc Diabetol (2020

 For Finerenone:
Based on preclinical data and ARTS phase II program

Hyperkalaemia Yes Yes Rare in phase II studies

Tissue distribution Kidney > heart (at least 6-fold) Kidney > heart (~3-fold) Balanced distribution (1:1)
1A 1B

1B 2B
CKD→ many drugs, toxicity, interactions?
 Pezzarella. CJASN 2018

Pezzarella. CJASN 2018

Sharbaf FG. J Renal Inj Prev 2015
Rosner MH. NEHM 2017
 CONCLUSIONS

✓CKD is a prevalent disease, frequently unknown

✓CKD is associated with ↑ mortality

✓Renal function is mainly defined by GFR or albuminuria

✓Important to estimate correctly GFR to define CKD not over

or under diagnostic, to adapt treatments
 CONCLUSIONS

✓GFR can be measured but cumbersome daily

✓Equations allowing to estimate: CKD-EPI most validated, but

adjusting for 1.73m2

✓Combine creatinine + cystatine C to confirm CKD

✓Some populations still not well represented by equations

(pregnancy, obese++, older+++, cirrhosis)
 CONCLUSIONS
✓Ageing is problematic because physiological vs
pathological renal function decline difficult to differentiate

✓Other markers can help in identifying renal disorders, but

not useful yet for GFR estimation

✓Combination of biomarkers set?

✓Imaging development: MRI? Ultrasound?

Traynor J. BMJ 2006
Glassock. KI 2009