hypertensive kidney injury and the progression of … kidney injury and the progression of chronic...
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Hypertensive Kidney Injury and the Progression of Chronic Kidney Disease
Karen A. Griffin, M.D.Professor of Medicine
Loyola University Medical CenterRenal Section Chief
Edward Hines, Jr. V.A. Hospital
Hypertension in the United States75 million
< 0.5% ESRD
USRDS Annual Report
Susceptibility Patterns of Hypertensive Renal Damage
100 140 180 220 260
Systolic Blood Pressure (mmHg)
Rena
l Dam
age Malignant
NephrosclerosisDiabetic Nephropathy / Chronic Kidney DiseaseAccelerated GS
Benign Nephrosclerosis
Bidani and Griffin , Hypertension 2004; 44: 595-601
Loutzenhiser, Griffin, Williamson, Bidani Am J Physiol 2006; 90:R1153-R1167(Griffin et al, Am J Hypertens 2001;14:311-320; Bidani et al, Am J Physiol 1993;265:F391-398
r2=0.77 r2=0.59
Hypertensive Renal DamageSusceptibility Patterns in Experimental Models
100 140 180 220 260Average Systolic BP, mmHg
0
25
50
Ren
al D
amag
e Sc
ore
SHRsp (n=10)SHRsp + NaCl (n=18)
SHR (n=9)SHR + NaCl (n=16)
RK-I (n=16)
Sprague-DawleyControl (n=7)
Remnant Kidney Model of CKD(5/6 Ablation)
• Compensatory Hyperfiltration and Hypertrophy
• Hypertension
• Proteinuria
• Progressive GS
Loutzenhiser, Griffin, Williamson, Bidani Am J Physiol 2006; 90:R1153-R1167Griffin et al, Am J Hypertens 2001;14:311-320; Bidani et al, Am J Physiol 1993;265:F391-398
r2=0.77 r2=0.59
Hypertensive Renal DamageSusceptibility Patterns in Experimental Models
100 140 180 220 260Average Systolic BP, mmHg
0
25
50
Ren
al D
amag
e Sc
ore
SHRsp (n=10)SHRsp + NaCl (n=18)
SHR (n=9)SHR + NaCl (n=16)
RK-I (n=16)
Sprague-DawleyControl (n=7)
Vasodilation
Bidani et al. AJP 252: F1003-F1010, 1987; Griffin et al, JCI 96: 793-800, 1995; Griffin et al, KI 55: 1849-1860, 1999; Bidani et al. AJP 285: F113-F120, 2003
Renal Autoregulation and Susceptibility to Hypertensive Damage
Rena
l Blo
od F
low
(%)
Arterial Pressure, mmHg
50
100
150
200
60 90 120 150 180 210 240
Susceptibility Patterns of Hypertensive Renal Damage
100 140 180 220 260
Systolic Blood Pressure (mmHg)
Rena
l Dam
age Malignant
NephrosclerosisDiabetic Nephropathy / Chronic Kidney DiseaseAccelerated GS
Benign Nephrosclerosis
Bidani and Griffin , Hypertension 2004; 44: 595-601
SHRsp Model of Malignant Nephrosclerosis(Prevention)
Griffin KA et al., Hypertension 2014;64:801-7
SHRsp Model of Malignant Nephrosclerosis(Prevention)
Griffin KA et al., Hypertension 2014;64:801-7
Ren
al D
amag
e Sc
ore
SHRsp Model of Malignant Nephrosclerosis(Repair)
Griffin KA, et al., Hypertension 2014;64:801-7
SHRsp Model of Malignant Nephrosclerosis(Repair)
Griffin KA, et al., Hypertension 2014;64:801-7
Remnant Kidney Model of CKD(5/6 Ablation)
• Compensatory Hyperfiltration and Hypertrophy
• Hypertension
• Proteinuria
• Progressive GS
Hyperfiltration vs. Hypertension
Pathogenesis of Glomerulosclerosisin Renal Mass Reduction Models
Griffin et al, JASN 1994; 4: 2023-2031
Griffin et al, JASN 1994; 4:2023-2031
Pathogenesis of Glomerulosclerosisin Renal Mass Reduction Models
Griffin et al, JASN 1994; 4: 2023-2031
Pathogenesis of Glomerulosclerosisin Renal Mass Reduction Models
• Normal Pregnancy (AJKD 1989; 290-298)• Renal Transplant Donors (NEJM 2009; 360:459-469)
Hyperfiltration in Normotensive States
Minimal glomerulosclerosis
QA, Kf (GC Volume)
Hypertensive States: PGC, but Kf due to a reciprocal relationshipAJP 1980; 239:F171-F186; AJP 1981; 240:F245-254; JCI 1986; 77:1993-2000
Bidani, et al. KI 1990; 38:28-38; Griffin, et al. JASN 1994; 4:2023-2031.
Griffin, et al. AJP 2008; 294:F685-F696
SPONTANEOUSLY HYPERTENSIVE RAT RENAL ABLATION BY INFARCTION RENAL ABLATION BY EXCISIONAVE. SYST. BP: 214 mm Hg AVE. SYST. BP: 214 mm Hg AVE. SYST. BP: 133 mm Hg
INTACT AUTOREGULATION IMPAIRED AUTOREGULATION IMPAIRED AUTOREGULATIO
EFFECTS OF HYPERTENSION AND IMPAIRED AUTOREGULATION ON CKD PROGRESSION (8 WEEKS – Hematoxylin/Eosin)
Venkatachalam, et al., Am J Physiol. 2010; 298: 1078-1094
Vasodilation
Bidani et al. AJP 252: F1003-F1010, 1987; Griffin et al, JCI 96: 793-800, 1995;Griffin et al, Am J Physiol Renal Physiol. 2004;286:F1136-43; Bidani et al. AJP 285: F113-F120, 2003
Renal Autoregulation and Susceptibility to Hypertensive Damage
Rena
l Blo
od F
low
(%)
Arterial Pressure, mmHg
50
100
150
200
60 90 120 150 180 210 240
Griffin et al, JCI 1995; 96:793, KI 1999; 55: 1849, Hypertens 2001; 37: 1268,Bidani et al, Kidney Int 2000; 57: 1651
0 2 5 5 0 7 5 1 0 0 1 2 5 1 5 080
120
160
200
Ave
rage
Sys
tolic
BP,
mm
Hg
0
10
20
30
40
HIR
D S
core
RK-I (n=16)
P <0.01 maximum vs RK-I
**
SHRsp (n=27)
Bidani et al, Am J Physiol 1993;265:F391-398; Griffin KA, et al., Hypertension 2014;64:801-7
Ren
al D
amag
e Sc
ore
Bidani et al, Am J Physiol 1993;265:F391-398; Griffin KA, et al., Hypertension 2014;64:801-7;Polichnowski, et al. Am J Physiol 2015; 308:F252-F260
Ren
al D
amag
e Sc
ore
100 125 150 175 200 225 250Average SBP, mmHg
0
25
50
75
Com
posi
te H
IRD
Sco
re
SHRsp (n=27)RK-I (n=16)
Angiotensin II (n=19)
Quantitative Relationship BetweenBP and Renal Injury
Bidani et al, Am J Physiol 1993;265:F391-398; Griffin KA, et al., Hypertension 2014;64:801-7;Polichnowski, et al. Am J Physiol 2015; 308:F252-F260
Ren
al D
amag
e Sc
ore
Angiotensin II10 seconds
10 seconds
Polichnowski AJ et al: Am J Physiol 2013; 305:F1074-F1084
BP – RBF Relationships in Conscious Angiotensin II vs. Phenylephrine-induced Hypertensive Rats
Susceptibility to Hypertensive Renal Damage
Efferent Arteriole
Glomerular CapillaryPressure (45-50 mmHg)
NOS Expression in the Renal Microvasculature
nNOSeNOS
Bachmann, et al., Am J Physiol 1995; 268:F885-898
Kriz and Bachmann J Cardiovasc Pharm 1985; 7: S24-30;Elger, et al., Adv Anat Embryol Cell Biol 1998; 139:1-98
Ang II vs. L-NAME-induced Hypertension
• Ang II-induced hypertension exhibits a diminished susceptibility to renal injury as compared to L-NAME-induced hypertension.
• BP – RBF relationships in conscious Ang II-infused rats suggests this is likely due to reduced transmission of elevated systemic BP to the renal microvasculature.
Polichnowski, et al. Am J Physiol 2015; 308:F252-F260
Ren
al D
amag
e Sc
ore
100 120 140 160 180 200
Systolic BP, mmHg
Ren
al D
amag
e
Hypertensive Renal Damage(Impact of Susceptibility and BP Differences)
Griffin KA and Bidani AK, Clin J Am Soc Nephrol 2006; 1(5):1054-1065
Anil Bidani, M.D.Maria Picken, M.D., Ph.D. Loyola University Med Ctr.and Hines VA Hospital
Aaron Polichnowski, Ph.D.East Tennessee State University & James H. Quillen VA Hospital
Rodger Loutzenhiser, Ph.D.University of Calgary
Manjeri Venkatachalam, M.D.Univ. of Texas, San Antonio
Geoffrey Williamson, Ph.D.Illinois Institute of Technology
Collaborators
Grant Support: NIH Grants: DK-40426 and DK-61653 Department of Veterans Affairs Merit Review Award
Renal Circulation: Pressure Profiles
Ofstad and Aukland: Renal Circulation. The Kidney: Physiology and Pathophysiology. (Eds). Seldin and Giebisch. 1985
Griffin et al, JASN 2000; 11:497- 506
MICROPUNCTURE AND MORPHOMETRIC DATA AT 3 WEEKS
AP GFR SNGFR PGC Kf Glom Vol mmHg ml/min/kg nl/min mmHg nl/sec/mmHg µ-3x10-6
Sham 105+2 39+0.3 38.4 46.3+0.8 0.04+0.002 1.1+0.04(n=10)
RK-NX 5/6 104+3 2.7+0.2* 78.3* 50.5+0.9* 0.06+0.008* 1.7+0.1*(n=10)
RK-I 5/6 136+3*δ 2.2+0.3* 72.9* 55.6+1.1*δ 0.05+0.006 1.9+0.1*(n=10)
*p < .01 compared to control, δ p < .01 compared to RK-NX 5/6
Pathogenesis of Glomerulosclerosisin Renal Mass Reduction Models
Griffin et al, JASN 2000; 11:497- 506
MICROPUNCTURE AND MORPHOMETRIC DATA AT 3 WEEKSAP GFR SNGFR PGC Kf Glom Vol
mmHg ml/min/kg nl/min mmHg nl/sec/mmHg µ-3x10-6
Sham 105+2 39+0.3 38.4 46.3+0.8 0.04+0.002 1.1+0.04(n=10)
RK-NX 5/6 104+3 2.7+0.2* 78.3* 50.5+0.9* 0.06+0.008* 1.7+0.1*(n=10)
RK-I 5/6 136+3*δ 2.2+0.3* 72.9* 55.6+1.1*δ 0.05+0.006 1.9+0.1*(n=10)
*p < .01 compared to control, δ p < .01 compared to RK-NX 5/6
Pathogenesis of Glomerulosclerosisin Renal Mass Reduction Models
Griffin et al, JASN 2000; 11:497- 506
MICROPUNCTURE AND MORPHOMETRIC DATA AT 3 WEEKSAP GFR SNGFR PGC Kf Glom Vol
mmHg ml/min/kg nl/min mmHg nl/sec/mmHg µ-3x10-6
Sham 105+2 39+0.3 38.4 46.3+0.8 0.04+0.002 1.1+0.04(n=10)
RK-NX 5/6 104+3 2.7+0.2* 78.3* 50.5+0.9* 0.06+0.008* 1.7+0.1*(n=10)
RK-I 5/6 136+3*δ 2.2+0.3* 72.9* 55.6+1.1*δ 0.05+0.006 1.9+0.1*(n=10)
*p < .01 compared to control, δ p < .01 compared to RK-NX 5/6
Pathogenesis of Glomerulosclerosisin Renal Mass Reduction Models
Griffin et al, JASN 2000; 11:497- 506
MICROPUNCTURE AND MORPHOMETRIC DATA AT 3 WEEKSAP GFR SNGFR PGC Kf Glom Vol
mmHg ml/min/kg nl/min mmHg nl/sec/mmHg µ-3x10-6
Sham 105+2 39+0.3 38.4 46.3+0.8 0.04+0.002 1.1+0.04(n=10)
RK-NX 5/6 104+3 2.7+0.2* 78.3* 50.5+0.9* 0.06+0.008* 1.7+0.1*(n=10)
RK-I 5/6 136+3*δ 2.2+0.3* 72.9* 55.6+1.1*δ 0.05+0.006 1.9+0.1*(n=10)
*p < .01 compared to control, δ p < .01 compared to RK-NX 5/6
Pathogenesis of Glomerulosclerosisin Renal Mass Reduction Models
Hypertension 65:510-516, 2015