Detecting the frail kidney with RFR

F. Husain-Syed

Nephrology, Pulmonology and Intensive Care Medicine - Giessen/Germany

Vicenza CourseVicenza, May 29, 2019

Faeq Husain-Syed

Employer: University Clinic Giessen School of Medicine and Medical Science, Germany

Disclosures: None

Westland R et al. Clin J Am Soc Nephrol 2013Botev R et al. Clin J Am Soc Nephrol 2009

What is “normal“ renal function and how should we measure GFR

Inulin-GFR (ml/min/1.73 m2) Inulin-GFR (ml/min/1.73 m2)

Seru

m c

reat

inin

e(m

g/d

l)

Seru

m c

reat

inin

e(m

g/d

l)

• Accepted as the best overall index of renal function

• GFR varies according to age, sex, body size

• GFR decrease generally precedes the onset of clinical renal failure

• Persistent GFR decrease indicates CKD

GFR <60 ml/min/1.73 m2 associated with increased cardiovasc. events & mortality

• Abrupt GFR reduction usually indicates AKI

Glomerular Filtration Rate

Go AL et al. New Engl J Med 2004

GFR Determinants: Age

Stevens LA et al. New Engl J Med 2006

Inu

lin-G

FR (

ml/

min

/1.7

3 m

2)

Inu

lin-G

FR (

ml/

min

/1.7

3 m

2)

Age (yr) Age (yr)

Men Women

Serum Creatinine and Measured GFR

Iohexol-GFR (ml/min/1.73 m2)

Seru

m C

reat

inin

e(m

g/d

l)

Insensitive

Transitional

Sensitive

Adapted from: Porrini E et al. Nat Rev Nephrol 2018

Insensitive

Transitional

Sensitive

Adapted from: Porrini E et al. Nat Rev Nephrol 2018

Serum Creatinine and Measured GFR

SCr 1.5 mg/dl is associated with mGFR 30 – 90 ml/min (n=3,146 patients)

Iohexol-GFR (ml/min/1.73 m2)

Seru

m C

reat

inin

e(m

g/d

l)

Adapted from: Porrini E et al. Nat Rev Nephrol 2018

Serum Creatinine and Measured GFR

Renal Reserve

Baseline GFR = Fasting GFR

Total GFR = Fasting GFR + Renal Reserve

CKDDetection Baseline Maximal

Iohexol-GFR (ml/min/1.73 m2)

Seru

m C

reat

inin

e(m

g/d

l)

GFR: Regulatory Mechanismsin Physiologic & Pathological Conditions

Adapted from: Stevens LA et al. New Engl J Med 2006

Vasodilation (↓GFR) NO Histamine ACEi / ARB

Vasodilation (↑GFR) ANP Glucagon, amino acids Prostaglandin, dopamine

Afferentarteriole

Vasoconstriction (↓GFR) NSAIDs Renal artery stenosis

Vasoconstriction (↑GFR) ANP Angiotensin II Norepinephrin

Efferentarteriole

Mean Arterial Pressure (mmHg)

High

Low

Intr

aglo

m. P

ress

ure

Range ofauto-

regulation

Normal

GFR Determinants: Renal Blood Flow vs. Venous Pressure

Ravera M et al. J Am Soc Nephrol 2006

Renal Perfusion Pressure = Renal Blood Flow – Central Venous Pressure

Damman K et al. J Am Coll Cardiol 2009Ravera M et al. J Am Soc Nephrol 2006

Mean Arterial Pressure (mmHg)

High

Low

Intr

aglo

m. P

ress

ure

Normal

Hypertension + CKD

Hypertension

CVP (mmHg)

eGFR

(m

l/m

in/1

.73

m2)

Ideal CVP

GFR Determinants: Renal Blood Flow vs. Venous Pressure

Renal Perfusion Pressure = Renal Blood Flow – Central Venous Pressure

GFR Determinants: Nephrons Development & Age

Kuhlmann U. Nephrologie 2008Denic A et al. J Am Soc Nephrol 2017

Age (yr)Postmentrual age (wks)

No new nephrons formed in human kidneys after 36 weeks’ gestation

Biodiversity: number of nephrons in humans

600.000 – 1.500.000

Lower nephron number implies: Reduced glomerular volume Reduced surface filtration area Impaired tubular function

–> Renal mass affects “renal frailty” or “renal susceptibility to insults”

Number of nephrons (x106)

GFR Determinants

Factors affecting GFR

Physiological or pathological

demand

Drugs

Disease

DietRenal mass

Adapted from: Molitoris B. Am J Kidney Dis 2017

Inulin-GFR (ml/min/1.73 m2)

8AM 2PM 8PM 2AM 8AM 0

20

40

60

80

100

120

140

160

GFR Variations Throughout the Day

Average GFR for 24 hrs: 100 ml/min/1.73 m2

Baseline GFR: 90 ml/min/1.73 m2

Maximal GFR: 150 ml/min/1.73 m2

Renal Reserve: 60 ml/min/1.73 m2

Bosch JP et al. Am J Med 1983

Cre

atin

ine

Cle

aran

ce (

ml/

min

/1.7

3 m

2)

7AM 12noon 5PM 10PM 7AM 0

20

40

60

80

100

120

140

160

Creatinine Clearance Throughout the Day

102 17

118 15 125 19

96 11

24 hrs urine collection measures average daily CrCl

Healthy Vegetarian Diabetic Pregnant W. CKD

Baseline GFR in HumansG

FR (

ml/

min

/1.7

3 m

2)

180

160

120

100

80

60

40

20

0

100 50 0Functional Renal Mass (%)

180

160

140

120

100

80

60

40

20

0

Maximal GFR

Renal functional reserve

Adapted from: Sharma A et al. Nephron Clin Pract 2014

Baseline GFR

Maximal single-nephron hyperfiltrationW

ho

leK

idn

eyG

FR (

ml/

min

/1.7

3 m

2)

100 50 0Functional Renal Mass (%)

180

160

140

120

100

80

60

40

20

0

Maximal GFR

Renal functional reserve

Wh

ole

Kid

ney

GFR

(m

l/m

in/1

.73

m2)

Adapted from: Sharma A et al. Nephron Clin Pract 2014

Baseline GFR

SCr

6

5

4

3

2

1

0

Seru

m C

reat

inin

e(m

g(d

l)

Drugs HypertensionPregnancy SepsisExercise AnemiaHigh attitude HemorrhageStress echo Ischemia

Drugs DiabetesPregnancy CKDHigh-protein diet AKIAging Cardiorenal syndromeHigh CO Hyperfiltration

Organ Reserve

Normal conditions Physiologic stress Pathologic stress

Ronco C at al. Critical Care Nephrology 3rd edition 2018

Functional reserve utilization

High protein meal / Amino acid infusion

GFR Increase after Stress Test

Gabbai F. Curr Opin Nephrol Hypertens 2018

Raised plasma amino acid concentration

AA filtered and stimulate proximal tubular absorption

AA change sensitivity of macula densa –> altered tubular Na/K concentration –> release NO, prostaglandins & glucagon –> dilation afferent arteriole –>

increased RBF & GFR

Maximal CrCl1g protein

powder

200

180

160

140

120

100

80

CrC

l(m

l/m

in/1

.73

m2)

Calculation of CrCl following different doses of protein load• 1 g/kg BW oral meat• 2 g/kg BW oral meat• 1 g/kg protein powder

Basel. CrCl: 100 ml/min/1.73m2

Max. CrCl: 140 ml/min/1.73m2

–> RFR: 40 ml/min/1.73m2

Optimizing a Kidney Stress Test to Evaluate Renal Functional ReserveSharma A, Zaragoza JJ, Villa G, Ribeiro LC, Lu R, Sartori M, Faggiana E, M, de Cal M, Virzi GM, Corradi V,

Brocca A, Husain-Syed F, Brendolan A, Ronco C.

MaximalCrCl

1g meat

Sharma A et al. Clin Nephrol 2016

Baseline CrCl

Maximal CrCl

2g meat

Protein load (red meat)

Creatinine

Inulin

180

160

140

120

100

80

60

40

20

0 1 2 3 4 hours

Cle

aran

ce (

ml/

min

)

Bosch JP et al. Am J Med 1983De Moor B et al. Clin Kidney J 2018

Maximal GFR• Meat 2–3 hours• Protein powder 1,5-2 hours• IV amino acids 1 hour

Baseline GFR Max GFR

Stimulation:• High protein• Hyperfiltration states

(pregnancy)

RFR

120 160Normal kidney, non-vegetarian

80 160Normal kidney, vegetarian

90 110Elderly normal kidney

48 50CKD

110 120Solitary normal kidney

Sharma A et al. Nephron Clin Pract 2014

Magri P et al. Circulation 1998

In heart failure: ↑RAAS activity (vasoconstriction) and ↓glomerular NO (vasodilation)

ACEi/ARB decrease angiotensin II formation and increase NO through kinin system

Early Impairment of Renal Hemodynamic Reserve in Patients With Asymptomatic Heart Failure Is Restored by Angiotensin II Antagonism

Magri P, Rao MAE, Cangianiello S, Bellizzi V, Russo R, Mele AF, Andreucci M, Memoli B, De Nicola L, Volpe M

–> RFR absent in heart failure

–> ACEi/ARB restore vasodilatory response to amino acids

Kidney Stress Test – Protein Load

UV UV,UCr &SCr UV,UCr &SCr UV UV,UCr &SCr UV,UCr &SCr UV,UCr &SCr

Oralwater20ml/kgBW

ReplaceUVwithoralwater1:1

ReplaceUVwithoralwater1:1

ReplaceUVwithoralwater1:1

ReplaceUVwithoralwater1:1

ReplaceUVwithoralwater1:1

ReplaceUVwithoralwater1:1

Oralproteinload1.2g/kgBW

1hr

30min 30min

Preparation:

2 days before salt- and low-protein food!

ACE inhibitors or ARB should be paused at least 2 days before, and diuretics on the day of the study. NSAIDs should be avoided for at least 3 days.

On the day of examination, the patient should drink at home 1/4 to 1/2 l of unsweetened fruit tea or water and eat a piece of bread. No caffeine-containing beverages allowed.

UV UV,UCr &SCr UV,UCr &SCr UV UV,UCr &SCr UV,UCr &SCr UV,UCr &SCr

Oralwater20ml/kgBW

ReplaceUVwithoralwater1:1

ReplaceUVwithoralwater1:1

ReplaceUVwithoralwater1:1

ReplaceUVwithoralwater1:1

ReplaceUVwithoralwater1:1

ReplaceUVwithoralwater1:1

Oralproteinload1.2g/kgBW

1hr

30min 30min

Baseline GFR Maximal GFR

Adults with normal eGFR undergoing elective cardiac surgery, n=110

Preoperative RFR measurement

→ Patients with RFR ≤15 ml/min/1.73 m2 are 11.8 more risk to develop AKI

(95% CI 4.6−29.9; p<0.001)

Husain-Syed F et al. Ann Thorac Surg 2018

Preoperative RFR predicts AKI after cardiac surgery

27.0 ± 8.6

15.5 ± 8.7

AKI (–) AKI (+)

RFR

(m

l/m

in/1

.73

m2)

AKI (–) AKI (+)

Intact RFR Deficient RFR CKD

Recovery

Partial Recovery

Ren

al F

un

ctio

n

Sharma A et al. Clin Nephrol 2016

Subclinical Clinical

Time

AKI

AKI

AKI

AKI & Renal Recovery

Prowle J et al. Clin J Am Soc Nephrol 2014

No AKI AKI stage 1 AKI stage 2 AKI stage 3

Serum Creatinine as Indicator for Follow-Up after AKI

AdmissionPeakDischargeFollow-up

Versus Follow-up: NS p>0.05; * p<0.05; ** p<0.01

10

5.0

2.0

1.0

0.5

0.2

Seru

m C

reat

inin

e (m

g/d

l)

-20

-10

010

20

RF

R (

ml/m

in/1

.73

m2)

No AKI Subclinical AKI KDIGO stage 1 KDIGO stage 2 and 3

RFR loss after each type of AKI

+p=0.8*p<0.001

No AKI Subclinical AKI AKI stage 1 AKI stages 2-3[TIMP-2]x[IGFBP7] (+)

Decrease of RFR 3 months after cardiac surgery

20

10

0

−10

−20

−delta 30.1%*

−delta 52.9%*−delta 27.5%*

−delta 1.0%+

RFR

(m

l/m

in/1

.73

m2)

Husain-Syed F et al. Nephrol Dial Transplant 2018

Persistent decrease of RFR in patients after cardiac surgery-associated AKI despite clinical recovery

Value of preoperative RFR to predict risk of AKI after cardiac surgery

Baseline GFR 106 ml/min/1.73 m2

Maximal GFR 130 ml/min/1.73 m2

Prospective multicentre study

DESIGN: Preoperative RFR in elective CS patients with normal eGFR

PARTICIPANTS: 350 (anticipated)

METHODS: Different measures of GFR (including iohexol)

OUTCOMES: Is preoperative RFR associated with postoperative AKI?

STATUS: Recruiting

--> RFR 24 ml/min/1.73 m2

Potential Clinical Utility of RFR

• Assessing baseline and progression of renal disease in high-risk patients

• Before high-risk procedures: Identify patients who are likely to benefit

from preventive measures or use biomarkers for early detection of AKI

• After AKI: discriminate apparent full recovery (normal baseline GFR but

↓RFR) vs. full recovery (normal baseline GFR and RFR)

• Identify borderline kidney donors, who are likely to develop decreased

renal function after donation

Conclusions (1)

• Baseline GFR is not a fixed function

• GFR may be normal despite partial loss of nephrons

• Capacity of increasing GFR in response to protein load describes the

presence of RFR

• Loss of RFR may result from nephron loss and/or loss of autoregulation

and altered tubular glomerular feedback

Conclusions (2)

• RFR has been increasingly used to evaluate filtration capacity in renal

transplant, kidney donors, solitary kidney, diabetes, pregnancy

• RFR valid prognostic factor for development of AKI / long-term renal

outcome after AKI?

• Returning baseline GFR after AKI to normal may not mean full renal

recovery

• In early phases of CKD, GFR may be normal but RFR is progressively lost