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