1、 Chong Myung Kang,M.D.Department of Internal Medicine Hanyang University HospitalA.The Role of the Kidney in HypertensionB.Hypertension as a Cause of Renal Disease C.Hypertension as a Risk Factor for the Progression of Renal DiseaseD.Hypertension as a Consequence of Renal Disease 1.Pressure-Volume R
2、egulation2.Congenital Oligonephropathy3.Renal Transplantation Studies4.Salt and HypertensionFig.2.Predicted Long-term effects of a peripheral vasoconstrictor that has a relatively week effect on pressure natriuresis.The normal curve(Solid line)is compared with the vasoconstrictor curve(dash line).In
3、itially,the vasoconstrictor would cause natriuresis,because increased peripheral vascular resistance elevates arterial pressure(from point A to point B)above the set-point for balance between intake and output of sodium due to increased.However,increased arterial pressure would cause a transient nat
4、riuresis and a reduction in extracellular fluid volume until arterial pressure eventually stabilized at a level(point C)at witch sodium intake and output are balanced.Fig.3.Proposed mechanism of pressure natriuresislMedullary blood flow(MBF)comprise only 1%of RBF,but important effect on pressure-nat
5、riuresislEndocrine¶crine factors(renal nerve,Ang II prostaglandin,ANP,NO,kinin,vasopressin modulate RPP&urine excretion by regulation of medullary blood flow lReduce MBF;sympathetic N stimulation,CO inhibition,kinin antagonist,NO synthase inhibition,Ang II,AVP-raise BPlIncrease MBF;ANP,prostagla
6、ndin,bradykinin,acetylcholine,CEI,Ca blocker-lowering BPAbnormal pressure-natriuresis in essential hypertension1.Increased preglomerular resistance widespread vasoconstriction of preglomerular vessels(arteriosclerosis,vasoconstrictors)-relieved with Ca blockers2.Increased tubular reabsorption excess
7、ive mineralocorticoid,Ang II (Salt-sensitive;depend on salt intake)3.Decreased glomerular capillary filtration coefficient(Kf)Essential HP with subtle dysfunction in glomerular capillary membrane,glomerulonephritis4.Reduced number of functioning nephrons Hyperfiltratioh-glomerulosclerosisFig.4.Stead
8、y-state relationships between arterial pressure and urinary sodium ecreation and sodium intake for normal kidney and four types of renal dysfunction that cause hypertension:decreased kidney mass,increased reabsorption in distal and collecting tubules,reduction in glomerular capillary filtration coef
9、ficient(Kf),and increased preglomerular resistance.lLow birth weight baby-higher incidence of hypertension in maturitylFewer nephrons,smaller kidney to body size (Japanese,African-American;adapted to less salt&water in tropical area-HP in salt replete state)lNephron number;genetic,conditions in uter
10、o (300,000-1,000,0000;low socioeconomic state,rat experiment,SHR)lLow birth weight,short stature;higher incidence of NIDDM,nephropathy in IDDMlHypertension can travel with kidneylF1 hybrids(F1H)from WKY&SHR;After bilateral nephrectomy,CEI treated SHR&WKY kidney transplanted to F1H Recipient of SHR-H
11、P,recipient of WKY-normal No difference between 2 group in BUN,RBF,GFRlGenetic predisposition for HP in donors is required to elicit post-transplantation HPlSHR;decreased capacity to excrete dietary NalThus,intrinsic renal mechanism play a major role in manifestation of primary hypertensionFig.5.Eff
12、ects of renal cross-transplantations on systolic blood pressure in five different animal medels of genetic hypertension.A.Normotensive recipients received a kidney from hypertensive donors.B.Hypertensive recipients received a kidney from normotensive donors.Symbols are:()Dahl salt-senstive hypertens
13、ive rats;()Milan hypetensive rats and Milan normotensive rats;()Prague hypertensive rats and Prague normotensive rats;Normotensive Wistar Kyoto rats(donors),spontaneously hypertensive rats and F1 hybrids(recipients)bred from the first two strains;()normotensive Wistar-Kyoto rats(donors),stroke-prone
14、 spontaneously hypertensive rats(donors)and F1 hybrids(recipients)bred from the first two strain.Fig.6.Blood pressure in human renal graft recipients at one year after transplantation.Based on indirect evidence,donors were assumed to have been normotensive()or hypertensive().The differences in blood
15、 pressure between recipients of a kidney from normotensive and hypertensive donor occurred despite more vigorous antihypertensive treatment in the latter.lAberrant response of tubuloglomerular feedback (TGF)to salt load is responsible for essential HPlAfferent arteriole contract or relax in response
16、 to inc.or dec.in macula densa Cl-delivery(autoregulation of RBF)lFine tuning of SNGFR through TGF Low salt intake-dec.afferent arteriolar resistance&TGF -maintain GPF&Ang II inc.RE-maintain PGC-SNGFRlInability of kidney to excrete salt load is responsible for development of hypertensionFig.7.Autore
17、gulation of renal plasma flow and glomerular filtration rate.Note afferent arteriolar resistance(RA)is regulated by boyh myogenic response and tubuloglomerular feedback and angiotensin II(AngII)can selectively act on efferent resistance(RE)allowing the maintenance of SNGFR in the face of reduced ren
18、al perfusion pressure.lHP;aberrant TGF to salt load-very low salt intake;no HP(Yanomamo,Xingu,Papua New Guinea,Kenya-No hypertension)lHuman body system;adapted to salt depletion of terrestrial environment;excessive salt intake in civilization-essential hypertensionlSlow genetic change vs rapid envir
19、onmental changelMechanism of HP induced renal damage 1.Glomerular ischemia&hypoperfusion 2.Glomerular capillary HP&hyperperfusion -inc.SNGFR-transglomerular passage of protein-inc.influx of protein¯omolecule into mesangium-proliferation&inc.matrix -GlomerulosclerosislIncreased protein traffic in
20、to urinary space-increased protein reabsorption by proximal tubule-tubulointerstitial damage (NH3 production-C3 activate-trigger inflammatory response in interstitium,stimulate cell growth,hypertrophy,reactive O2 specieslProgression of renal disease correlate best with interstitial damagelLeakage of
21、 plasma component across GBM-activate MAC-GEC damage-disrupt normal GBM turnover-GBM damageFig.9.Mechanism whereby immune damage to the GBM results in the leakage of complement components to the epithelial side of the membrane.This may facilitate the assembly of the membrane attack complex on the ep
22、ithelial cell and disrupt the normal GBM turnover.l“Hypertensive nephrosclerosis”Myointimal hyperplasia,hyaline arteriosclerosis in small arteries&arterioles-progression to ESRD(30%of ESRD in U.S.A.)lHistory of HP at least 5 years,initially normal renal function&urinalysis,proteinuria 1g/daylPrimary
23、 renal parenchymal disease;abnormal urinalysis prior to onset of hypertensionlNo hypertensive nephrosclerosis in patients with BP controlled reduce intraglomerular pressure;more effective than Ca antagonist in antiproteinuric&preventing progression of renal diseaselCa antagonist;reduce preglomerular
24、 arterial resitance;inc.urinary albumin excretionFig.10.Possible hemodynamic mechanism of renal protection by calcium antagonists and ACE inhibitors.lJoint National Committee for Detection,Evaluation,and Treatment for High Blood Pressure;target blood pressure 130/85 mm Hg for patients with renal disease(not 140/90)lMDRD study;target BP depend on proteinuria Proteinuria 0.25 to 1.0 g/D;130/80(mean 98)1.0 g/D;125/75(mean 92)“Kidney is a causative organ for hypertension and target organ of hypertensive damage”
