Detecting the frail kidney with RFR - IRRIV-International ......Inulin-GFR (ml/min/1.73 m2)...
Transcript of Detecting the frail kidney with RFR - IRRIV-International ......Inulin-GFR (ml/min/1.73 m2)...
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