病理生理學課件：腎功能不全

RenalInsufficiency

腎功能不全

CRF→pathologicfracture？metastaticcalcification？（renalosteodystrophy

）RENALINSUFFICIENCYSection1

INTRODUCTION

Section2

BASICTACHEOFPATHOGENESISFORRENALINSUFFICIENCY

Section3

ACUTERENALFAILURESection4

CHRONICRENALFAILURE

Section5

UREMIA

Section1

INTRODUCTION

(overview)

(1)

excretoryfuction

toexcretewasteproducts,drugandtoxicsubstances;

(2)

regulatoryfunction

to

maintainhomeostasisofbodyfluids,electrolytes,andacid-basebalance;(3)

endocrineandmetabolicfunction

tosecreterenin,erythropoietin,activevitaminD,prostaglandin,kinin,andtodeactivateparathyroidhormone(PTH)andgastrinetc..

1.PhysiologicalfunctionsofKidneys2.

conceptionRenalinsufficiency

isapathologicalprocessinwhichtheseveredamageofrenalfunctionsleadtothecumulationofmetabolismproducts,drugsandpoisons,disordersofwater,electrolytemetabolism,acid-basebalance,andrenalendocrinefunction.

3.

causes

(1)renaldiseases(essential)(2)non-renaldisease（secondary）

systemicbloodcirculationdisorder,systemicmetabolicdisorder,immunediseases,physicalandchemicalfactors，urethralillness.4.

clinicmanifestations

edema,hypertension,oliguria,polyuria,flankpain,hematuria,proteinuriaetc.5.

classification

acuteandchronicrenalfailure.Section2BASICTACHEOFPATHOGENESIS

FORRENALINSUFFICIENCY

GRF（120ml/min）

ultrafiltrate

barometerGFR(glomerularfiltrationrate)=(differenceinhydrostaticpressure

–differenceinoncoticpressure)xpermeabilityxglomerularplasmaflowxglomerularcapillarysurfacearea

DysfunctionofGlomerularFiltration

Renalcorpuscle

Functionofmesangialcells:①contractileproperties；②supportaction；③phagocyticproperties；④secretingreninDysfunctionofGlomerularFiltration

1.DecreaseofRenalBloodFlow

300g20～30％80～160mmHg(prostaglandinsystem）

2.DecreaseofGlomerularEffectiveFiltrationPressure

Glomerulareffectivefiltrationpressure=intraglomerularcapillarypressure–(plasmoncoticpressure+tubularhydrostaticpressure)

60mmHg

(60%ofsystemicbloodpressure)

1025DysfunctionofGlomerularFiltration

3.DecreaseofGlomerularCapillarySurfaceArea

decreases(>50％)→GFR↓2million

4.

AlterationsofPermeabilityofGlomerularFiltrationMemberTheglomerulurfiltrationmemberisformedbyglomerularcapillaryendothelialcell,basementmembraneandpodocytes.

SizebarrierandChargebarrier

Inflammation,damageandimmunecomplexetc.mayinduceincreasedmembranepermeability,whichleadstohematuriaandproteinuria.RenalTubularDysfunction(1)DysfunctionofproximalConvolutedTubules

renaldiabeticurine,aminoacidurine,sodiumandwaterretentionandrenaltubularacidosisetc.(2)DysfunctionofHenle'sloop

polyuria,hypotonicorisotonicuria.(3)Dysfunctionofdistalconvolutedtubulesandcollectingducts

disordersofsodium,potassiummetabolismandacid-basebalance.

reabsorbtion,secretionandexcretionIschemia,infectionandpoisonsAldosterone,ADH,ANPandPTH

RenalEndocrineDysfunction

1.Renin–Angiotensin–Aldosteronesystem(RAAS)：

angiotensin-convertingenzyme（ACE）ACE2-Ang-(1-7)

boostingpressure

Renalhypertension;Na+andwaterretention.

2.Kallikreinkininprostaglandinsystem（KKPGS）：

depressurizationRenalhypertension

3.Erythropoietin(EPO)：

polypeptideRenalanemia

4.1a,25-dihydroxyvitaminD3[1,25-(OH)2ＶD3]

：

Hypocalcemia,Renalosteodystrophy

5.InactivationofPTHandgastrin：

Renalosteodystrophy,Digestiveulcer

Section3

ACUTERENALFAILURE

(ARF)

1.concept

Acuterenalfailure(ARF)isapathologicalprocess,whichischaracterizedbyadeteriorationofrenalfunctionoveraperiodofhourstodays,resultinginthefailureofthekidneytoexcretenitrogenouswasteproductsandtomaintainfluid,electrolytehomeostasisandacid-basebalance.

2.classification

(1)Dependonetiology

Prerenal

；Intrarenal；Postrenal

(2)Dependon

damagenature

Functional；Parenchymal；Obstructive

(3)Dependion

urinaryvolume

oliguric（most）；nonoliguric（afew）

introduction3.Cause（1）prerenalfactor

（renalischemia）

shock，stress，heartfailure，

hepaticfailureect.（2）renalfactor

acutetubularnecrosis（ATN）

①renalischemiaandreperfusioninjury

；②renalpoisons

；③abnormalitiesofbodyfluidfactors

acuterenalparenchymadisease

（3）postrenalfactor

renalstones,tumorofpelvic,prostatichyperplasiaorcancinoma

GlomerularfactorsGFR↓

1.RenalHypoperfusion(RenalIschemia)

(1)Decreaseof

renalperfusionpressure

(<50～70mmHg)

(2)Renalvasoconstriction

：

①excitationof

sympathetic-adrenomedullarysystem;②activationofRAAS;③decreaseofkinin-prostaglandinsynthesis；④increaseof

endothelin(ET);⑤decreaseofnitricoxide(NO)

(3)Renalvascularendothelialswelling

(4)Intrarenaldisseminatedintravascularcoagulation2.GlomerularInjuryPathogenesisofARF1.RenalTubularObstruction

2.Back-LeakageoftheGlomerularFiltrate

Renaltubularfactors

Pathogenesisofacuterenalfailure

RenalCellularInjuryandItsMechanismsin40sof20thcentury,ATNischaracterizedbyrenaltubulardamage.Othercells(endothelialcells,mesangialcellsetc.)

1.CellInjury（1）renaltubularepithelialcell

1）necroticlesion：

tubulorrhexicandnephrotoxic

2）apoptoticlesion（2）renalvascularendothelialcell①swelling；②microthrombusformation；③decreasingofglomerularendothelialwindow；④imbalanceofvasoconstrictorandvasodilatorcytokine（3）mesangialcell

Its

constructionresultsindecreaseoffiltrateareaandKf.2.MechanismsofCellDamage(1)ReductionofATPsynthesisanddysfunctionofionpumps

(2)Increaseofoxygenfreeradical

(3)DecreaseofreducedGlutathione(GSH)

GSHmayscavengefreeradical,maintainnormalproportionofsulfhydryl(-SH-)/disulfide(-SS-)andpreventtheactivationofphospholipase.

(4)Increasedactivityofphospholipases

(5)CytoskeletalStructuralChanges

Duringrenalischemiaandpoisoning,cytoskeletalstructurewillmarkedlychangeduetoreductionofATPgeneration.Forexample,uncouplingofactincontrollingreabsorptiveareaofmicrovilli,breakageoflinkbetweenmyofilamentnetworksandcellularmembrane,changeofactionbetweenankyrinandspectrinwillleadabnormalityofcellularstructureandmembranepolarity,surfaceareaofcellularmembrane，andbreachofcontinuityofrenaltubularepithelium.

(6)Activationofneutrophilsandinflammatoryresponse

(7)Increaseincellapoptosis

（1）缺血缺氧的基因調節(jié)反應：

上調或下調相關基因，糖酵解通路各種酶、生長因子和NOS、環(huán)加氧酶、HO等，擴張血管和清除毒物等。

（2）應激蛋白的產生與激活：

缺血應激時熱休克因子形成三聚體，與DNA熱休克成分結合，激發(fā)HSP基因轉錄和蛋白貭合成。分子伴娘（molecularchaperone）作用，使正常細胞蛋白不受酶解，Na+-K+-ATP酶、肌動蛋白和其他細胞骨架重新復位。

（3）生長因子的作用：

上皮生長因子（EGF）、轉化生長因子(TGF)、胰島素生長因子（IGF）、血小板源性生長因子（PDGF）及纖維母細胞生長因子（FGF）等。它們與細胞膜特異性受體結合，激活細胞內酪氨酸激酶（tyrosinekinase）、絲裂原蛋白激酶(MAPK)或磷脂酰肌醇系統(tǒng)，促進細胞增生和組織修復。

（4）細胞骨架與小管結構的重建：

ARF恢復期，腎小管細胞骨架細胞間連續(xù)性恢復，它是膜極性恢復的前提。3．細胞增生與修復機制

缺血再灌注損傷后，近曲小管刷狀緣（brushborder）和極性（polarity）喪失，整合素（integrin）和Na+/K+–ATP酶重新分布到頂端表面（apicalsurface）。鈣、活性氧、嘌呤耗竭和磷脂酶，在形態(tài)學和極性改變及細胞死亡中發(fā)揮某種作用。細胞脫落到管腔，形成管型和管腔阻塞，參與GFR降低。損傷嚴重的腎可完全恢復其結構和功能。恢復期活細胞擴展（spreading）和去分化（dedifferentiation），將復制正常腎發(fā)育外觀。各種生長因子可能參與正常腎小管上皮再生。缺血性急性腎衰時腎小管細胞損傷和修復

PossibleRoleofNeutrophilActivationbyDialysisMembranesinIschemicAcuteRenalFailureAlterationsofMetabolismandFunction

Theoliguricstage

1.Urinousalterations

①oliguriaoranuria；②hyposthenuriaorisosthenuria；

③increaseofurinoussodium；④hematuria,albuminuriaandcylindruria

2.Waterintoxication

3.Hyperkalemia

4.Metabolicacidosis

5.Azotemia

Thepolyuricstage

>400ml/d

Themechanismofpolyuria:

①therenalbloodstreamandglomerularfiltrationfunctiongraduallygetright；②functionoftheneonatalrenaltubularepitheliaisstillimmature；③renalinterstitialedemafadeaway；④osmoticdiuresis.

Therecoverystage

UrinealterationinfunctionalandparenchymalARF

Hypovolrmia(functionalARF)AcuteTubularNecrosis(intrirenalARF)Sediment

BlandBroad，brownishgranularcasts,RBC，WBCanddenaturalizatedepithelialcell

Protein

Noneorlow

+～++++Urinesodium

（mEq/L）<20>30（40）Urineosmolality（mOsm/kg）>400（＞700mmol/L）<350（＜250mmol/L）Urinespecificgravity

＞1.020＜1.015Creatinineinurine/creatinineinblood

＞40∶1＜10∶1Diureticeffectofmannitol

goodworsePathophysiologicalBasisof

PreventionandTreatmentforARF(1)Thedrugscausingkidneyinjuryandnephrotoxinsmustbeusedcarefullyoravoided.(2)TheunderlyingcauseofARFshouldistreated,andfluidandelectrolyteimbalancesarecorrectedactively.(3)activetreatmentofelectrolyteimbalanceandacid-basedisorders;preventingandtreatinginfectiouscomplications.(4)UsethedrugsandagentsaimingatpathogenesisofARF;(5)Renalreplacementtherapymaybeprovidedbyperitonealdialysis,intermittenthemodialysis.

1.concept

CRFisdefinedasapermanentreductioninglomerularfiltrationrate(GFR)gressiveandirreversible2.FeaturesofCRF

①symptomslastinglongerthan3months;

②increasedBUNorserumcreatininedocumentedmonthsearlier.Aprevioussystemicdiseaseorahistoryofkidneydisease;

③normocyticnormochromicanemia;

④smallkidneys(lessthan10cm)onrenalultrasound.

diabeticnephropathy,amyloidosis,polycystickidney,ormalignanthypertensionmayhavenormal-sizedkidneys.Section3

CHRONICRENALFAILURE

(CRF)introductionEtiologyofCRFCausesofend-stagerenaldisease(ESRD)Accordingtooldschoolbook,chronicglomerulonephritisisthemostcommoncauseofCRF(about50～60％),buttherecentdataindicatethatDiabetesandhypertensionarethemostcommoncausesofCRFandend-stagerenaldisease(ESRD)Diseasethatcausepermanentlossofnephrons

ProgressiveStagesofCRF1.DiminishedRenalReserve(compensatory)2.Renalinsufficiency3.Renalfailure

4.End-stagerenalfailure(uremia)theclearancerateofendogenouscreatinine

PathogenesisofCRF1.ThemajorhypothesesonCRF

Bricker

(1)intactnephronhypothesis）

(2)glomerularhyperfiltrationhypothesis(3)trade-offhypothesis(4)Lesionoftubularandinterstitialcells2.Mechanismforlossofnephronfuction

EffectoftheInitialDiseases

byinflammatoryreaction,immunoreaction,urethralobstruction,macromolecularaggradation.

sn’tmajoycauseofCRFSecondaryProgressiveGlomerulosclerosis

Theriseofintraglomerularandsystemicbloodpressure,disturbancesinlipidmetabolism,upregulationofproinflammatorycytokinesandgrowthfactors,mesangialcellproliferation,mesangialexpansionwithmesangialfoamcellaccumulation,accumulationofextracellularmatrixcomponentsetc.allparticipateinglomerulosclerosisandinterstitialfibrosis.

3.Independentriskfactors

(1)activationofrenin-angiotensinsystem

AngIIisnotonlyavasoactivepeptide,butalsoatruecytokine

thatregulatescellgrowth,inflammationandfibrosis.AT1receptormediatesalltheclassicwellknowneffectsofAngII,suchaselevationofbloodpressure,vasoconstriction,increaseincardiaccontractility,aldosteronereleasefromtheadrenalgland,facilitationofcatecholaminereleasefromnerveendings,renalsodiumandwaterabsorption,andsoon.

inkidneyare1000-foldhigherthaninbloodAngIIplaysacriticalrolenotonlyintheregulationofGFR,butalsointhedevelopmentofglomerulosclerosisbyincreasingglomerularcapillarypressure.

viaAT1receptor,directlycausescellularphenotypicchanges,upregulatesthegeneexpressionofvariousbioactivesubstances,andactivatesmultipleintracellularsignalingcascadesincardiacmyocytes,fibroblasts,vascularendothelialandsmoothmusclecells,andrenalmesangialcells.Theseactionsparticipateinthepathophysiologyofvascularthickening,atherosclerosis,hypertrophyandproliferationinmesangialcellsandglomerulosclerosis.

Effectsofrennin-angiotensinsystemblockadeonthenephron(2)oxidativestresssOxygenradicalscontributetotheenhancedbasalvasculartone,tubuloglomerularfeedback,monocyte/macrophageinfiltrationandsensitivityofthevasculatureandtotheimpairedendothelium-dependentrelaxationinthediseasedkidney.Reactiveoxygenspeciesmayactassecondmessengersforseveraltranscriptionfactors,includingnuclearfactor(NF-kB),whichplaysacriticalroleintheactivationofmultiplegenesthatcontributetotheinflammatoryresponseandend-organdamage.Someoftherenalvasculardamageinhypertensionmaybeduetotheproinflammatoryactionsofoxygenradicalsinthekidney.Therearevarioussourcesforoxygenradicalformationindiabetes:①AngIIstimulatesvascularsuperoxideformationthroughactivationofNADPHoxidase;②hyperglycemiaisalsoamainsourceofoxygenradicalformationindiabetes.Elevatedplasmaglucoseconcentrationmayincreaseoxygenradicalproductionthroughglucoseautooxidation,theformationofadvancedglycosylationend-products,proteinkinaseCactivationandtheactivationofthepolyolpathway.IncreasedglucosesignificantlyincreasesvascularsensitivitytoAngII.

Renaldysfunctionisacentralcauseofhypertensionandacommonconsequenceofdiabetesmellitus.（3）蛋白尿（albuminuria）

進行性腎功能喪失的最后共同通路形成管型→阻塞腎小管→損害腎小管細胞和間貭；重吸收濾過蛋白→激活近曲小管上皮→蛋白應激反應→炎癥和血管活性基因表達上調。

(4)醛固酮

（aldosterone）傳統(tǒng)觀點，鹽皮質激素受體（mineralocorticoidreceptor，MCR），與蛋白復合物的“伴娘”相連（失活狀態(tài)）。當醛固酮結合遠曲腎小管上皮細胞的MCR時，伴娘釋放，受體-激素復合物轉入細胞核，啟動轉錄因子，調節(jié)基因表達，使上皮鈉通道磷酸化，Na+、水重吸收和泌K+。目前，很多證據(jù)提示，在心腦和血管等非上皮組織存在MCR并有活性。臨床研究顯示，血漿醛固酮水平與左心室肥厚、中風和腎功能障礙的嚴重程度高度相關。原發(fā)性高醛固酮血癥（primaryaldosteronism，PA）患者，醛固酮水平升高伴RAS其它組分抑制。醛固酮腺瘤的腎組織活檢，56%動脈硬化，46%間貭纖維化和腎小管萎縮（tubularatrophy）。醛固酮拮抗劑或腎上腺切除術，顯箸降低SHR的中風、蛋白尿和腎微血管損傷的發(fā)生率，但不伴有顯箸血壓降低。醛固酮也取消ACEI和AngIIRA在殘余腎高血壓模型的腎保護作用。因此，醛固酮應看作心血管疾病終末器官損傷的重要獨立風險因子。三、慢性腎衰時的機能代謝變化

早期：多尿（>2000ml/24h)，夜尿，低滲尿，蛋白尿、紅白細胞、管型等。

晚期：少尿和等滲尿(1.008～1.012)。

多尿機制：(1)原尿流速快；(2)滲透性利尿；(3)尿濃縮功能降低。

（髓袢血管少，易受損，Cl-主動吸收減少，髓質高滲形成障礙，尿濃縮功能降低）

2.水、電解質和酸堿平衡紊亂

1)鈉水代謝障礙水攝入↑→水潴留→肺水腫、腦水腫和心力衰竭；嚴格限制水攝入→脫水；限制鈉攝入→低鈉血癥；鈉攝入過多→鈉水潴留。

2)鉀代謝障礙早期血鉀多正常。低鉀血癥：①攝入↓；②吐瀉；③排鉀利尿劑。晚期高鉀血癥：①排鉀↓；②保鉀利尿劑；③酸中毒；④感染等使分解代謝增強；⑤溶血；⑥含鉀飲食或藥物攝入過多。

3)鎂代謝障礙晚期引起高鎂血癥。

4)鈣磷代謝障礙高血磷、低血鈣。

5)代謝性酸中毒①GFR下降；②腎小管排H＋和重碳酸鹽重吸收減少；③腎小管上皮細胞產NH3

減少。

1.尿的變化

4.腎性高血壓(1)鈉水潴留

腎臟排鈉水↓→鈉水潴留→血容量↑心輸出量↑→血壓↑

鈉依賴性高血壓（sodium-dependenthypertension）

(2)腎素分泌增多

慢性腎小球腎炎、腎動脈硬化癥等所致慢性腎衰→常伴RAAS活性↑→血管緊張素Ⅱ收縮小動脈，醛固酮↑導致鈉水潴留→血壓↑。

腎素依賴性高血壓（renin-dependenthypertension）

(3)腎臟降壓物質生成減少

腎單位大量破壞→激肽和PGE2↓

5.出血傾向皮下淤斑和粘膜出血。毒性物質抑制血小板功能：①血小板第3因子釋放受抑制；②血小板的粘著和聚集功能減弱。

6.腎性貧血

①促紅細胞生成素減少；②毒物抑制骨髓造血功能；③毒物使紅細胞溶血；④毒物抑制血小板功能引起出血；⑤腎毒物使腸道對造血原料吸收或利用障礙

。

3.氮質血癥常用內生肌酐清除率(尿中肌酐濃度×每分鐘尿量/血漿肌酐含量)判斷病情，它與GFR呈平行關系。MetastaticcalcificationMyocardialcalcificationpathologicfracturePathogenesisofrenalosteodystrophy

RenalosteodystrophyisaseriouscomplicationofCRF(especially,ofuremia),whichincludesrenalrickets(forchildren),adultosteomalacia,osteitisfibrosa,osteoporosis,osteosclerosis,etc.Pathogenesisofrenalosteodystrophy

一、尿毒癥毒素

二百多種代謝產物或毒性物質

1．尿毒癥毒素來源①正常代謝產物，如尿素、胍、多胺等；②外源性毒物，如鋁的潴留等；③機體代謝產生新的毒性物質；④正常生理活性物質濃度持續(xù)升高，如PTH等。

2．尿毒癥毒素分類

(1)小分子毒素(<500)如尿素、肌酐、胍類、胺類等。

(2)中分子毒素(500～5000)多為細胞和細菌的裂解產物等。

(3)大分子毒素(>5000)主要是血中濃度異常升高的PTH、生長激素等。Section3

uremiaUremiaisthemostseverestageofacuteorchronicrenalfailue.Besidesdisordersofwaterandelectrolytemetabolism,acid-baseimbalance,anddysfunctionofrenalendocrinefunction,thepatientswithuremiawillmanifestaseriesofautotoxicationsymptomscausedbyaccumulationofendogenouspoisons.

3．幾種常見的尿毒癥毒素

（1）胍類甲基胍毒性最強，引起嘔吐、腹瀉、肌肉痙攣、嗜睡、紅細胞壽命縮短及溶血等。胍基琥珀酸則可抑制血小板功能，促進溶血等。

（2）尿素可引起頭痛、厭食、惡心、嘔吐、糖耐量降低和出血傾向等。其代謝產物-氰酸鹽可使蛋白質發(fā)生氨基甲?；种圃S多酶活性，影響細胞功能。

（3）多胺包括精胺、精脒、尸胺和腐胺，引起厭食、惡心、嘔吐和蛋白尿，促進紅細胞溶解，抑制Na