임상의학개론 신장 성균관대학교삼성창원병원 신장내과이유지
신장의구조와기능
완두콩모양 위치 : 11 번째등뼈 (T11) 에서셋째허리뼈 (L3) 사이, 복강뒷벽의위쪽, 양쪽한쌍 크기 : 길이 11~12 cm 폭 5~6 cm 두께 2.5~3 cm 무게 : 성인남자 125~170 g 성인여자 115~155 g
피막 (capsule) 소엽사이동ㆍ정맥 (interlobular A. & V.) 활꼴동ㆍ정맥 (arcuate A. & V.) 엽사이동ㆍ정맥 (interlobar A. & V.) 콩팥엽 ( 신엽 renal lobe) 사람은 8-18 엽으로된다엽콩팥 (multilobar kidney). 속질 ( 수질 medulla) ( 콩팥피라미드 Renal pyramid) 속층 (inner medulla) 바깥층 (outer medulla) 콩팥동맥 (renal artery) 콩팥정맥 (renal vein) 작은술잔 ( 소신배 minor calyx) 큰술잔 ( 대신배 major calyx) 콩팥깔때기 ( 신우 renal pelvis) 겉질 ( 피질 cortex) 속질부챗살 (medullary ray) 겉질미로 (cortical labyrinth) 콩팥기둥 (renal column of Bertin) 요관 (ureter) 콩팥유두 (renal papilla)
겉질미로 (cortical labyrinth) 속질부챗살 (medullary ray) 소엽 (lobule) 겉질 (cortex) OSOM ISOM 바깥속질 (outer medulla, OM) 속속질 (inner medulla, IM)
콩팥단위 (nephron) 1. 콩팥소체 (renal corpuscle) - 사구체 (glomerulus), - 보우만주머니 (Bowman s capsule) 2. 근위곱슬세관 (proxiaml convuluted tubule) 3. 근위곧은세관 = 굵은내림부분 (proximal straight tubule = thick descending tubule) 4. 내림가는부분 (descending thin limb) 5. 오름가는부분 (ascending thin limb) 6. 원위곧은세관 = 굵은오름부분 (distal straight tubule=thick ascending limb) 7. 치밀반점 (macula densa) 8. 원위곱슬세관 (distal convoluted tubule) 9. 연결세관 (connecting tubule) 집합관 (collecting duct) 10. 겉질집합관 (cortical collecting duct) 11. 바깥수질집합관 (outer medullary collecting duct) 12. 속수질집합관 (inner medullary collecting duct) 3~6: 콩팥단위고리 (loop of Henle) 6~12: 원위콩팥단위 (distal nephron)
Renal corpuscle ( 콩팥소체 ) Afferent arteriole TAL Macula densa Efferent arteriole Bowman s capsule Parietal epithelial cells podocyte JG cells Glomerulus Mesangial cells & Mesalgial matrix Capsular space (Bowman s space) Endothelial cells Proximal tubule
Structure of renal corpuscle
콩팥여과관문 Glomerular filtration barrier Urinary space Filtration slit Podocyte processes Filtration slit diaphragm LRE LD LRI fenestrae Endothelial cell (cytoplasm) Glomerular capillary lumen Direction of flow of the plasma ultrafiltrate Glomerular basement membrane - Lamina rara externa - Lamina densa - Lamina rara interna
Glomerular filtration barrier Glomerular capillary endothelium ( 사구체모세혈관내피세포 ) Fenestrated (without diaphragm) endothelium: 유창모세혈관 내피창 (fenestrae): 직경 70-90 nm 사구체내피세포 : 세포표면에 polyanionic glycosaminoglycans and glycoproteins 이있어 negative surface charge 를띰
Glomerular filtration barrier Glomerular basement membrane ( 사구체기저막 ) Type IV collagen Heparan sulfate (negative charge) 가포함된프로테오글리칸 (proteoglycan) Laminin, fibronectin 과같은당단백질 (glycoprotein)
Glomerular filtration barrier Slit diaphragm of podocytes ( 발세포의여과틈새가로막 ) 구성단백질 : Nephrin, Neph1 and Neph2, FAT1 and FAT2, Podocin Interact with the actin cytoskeleton of podocyte foot processes Podocytes 와 slit diaphragm 표면에 polyanionic glycoproteins (e..g., podocalyxin) 이있어 negative charge 를띰
Glomerular filtration barrier
여과의조건 Size: 70,000 d Charge: negatively charged substances 는여과가잘안됨. Flexibility
Juxtaglomerular apparatus ( 사구체곁장치 ) Afferent arteriole TAL Macula Densa Extraglomerular mesangium Efferent arteriole Vascular pole ( 혈관극 ) 1. Afferent arteriole 2. Efferent arteriole 3. Macula densa 4. Extraglomerular mesangium JG cells 구성 1. 치밀반세포 (macula densa cells) - 높은원주형세포들이밀집 - 내강내 Na +, Cl - level 을측정하여 JG cell 에서의 renin 분비조절 2. 사구체방세포 (justaglomerular cells) - renin 생산분비 - intrarenal baroreceptor 로서역할을함 3. 사구체밖혈관사이막 (extraglomerular mesangium) - mesangial matrix & extraglomerular mesangial cells - MD 로부터의신호를 JG cell 또는 glomerular mesangial cell 로전달
Juxtaglomerular apparatus ( 사구체곁장치 ) 기능 : arterial blood pressure 조절 1. renin-angiotensin-aldosterone system 2. Tubuloglomerular feedback mechanism : 신혈류변동및사구체여과율변화에대하여민감하게반응하는자가조절기전 (autoregulation)
Na + 2 Cl - K + The effect of decreasing NaCl concentration at the macula densa is schematically shown to cause an increase of PGE2 in the JGA interstitium and an EP4-mediated release of renin from granular cells -> Na + 재흡수촉진
Na + 2 Cl - K + The effect of elevating NaCl at the macula densa is shown schematically to consist of an increase in the levels of adenosine in the JGA interstitium and adenosine 1 receptors-mediated constriction of the afferent arteriolar smooth muscle cells -> GFR 감소
근위세관 (proximal tubule) 2. 근위곱슬세관 (proximal convoluted tubule) 3. 근위곧은세관 (proximal straight tubule) - 여과된 70% water, glucose, Na, Cl, HCO3, K, P, amino acids 등의재흡수에관여 Brush border (microvilli)
Reabsorption by PT cells
Reabsorption by PT cells
헨레고리 (loop of Henle) Loop of Henle 3. 근위곧은세관 = 굵은내림부분 (Proximal straight tubule) 4. 내림가는부분 (descending thin limb) 5. 오름가는부분 (ascending thin limb) 6. 굵은오름부분 (thick ascending limb) Cortical nephron = Short-loop nephrons (60~70%) 헨레고리의가는부분에서 15% of the filtered water 재흡수 25% of the filtered NaCl, K, Ca, HCO3 재흡수 Juxtamedullary nephron = Long-loop nephrons (30~40%)
Thick Limb - Loop of Henle Sodium Reabsorption Tubular Lumen (urine) Ascending Thick Limb of the Loop of Henle epithelial cell Capillary Lumen (blood) Na + ATP 2K + 2 Cl - 3 Na + K + recycling K + + K + ROMK channel Cl - - Na + Ca +2 Mg +2 Paracellular Pathway
헨레고리의가는부분 최대농축뇨생성 : 수질간질의삼투압을높게유지 Countercurrent multiplication ( 반류증폭 ) 1. Descending limb: permeable to water (water channel, AQP1), low permeable to NaCl 2. Ascending thin limb: permeable to NaCl but not to water 3. Thick ascending limb: reabsorbs salt by active transport, impermeable to water -> primarily in long loops of Henle -> dilution and concentration of the urine.
Localization of renal aquaporins
Countercurrent mechanism
Papillary tip (inner medulla)
Maximum osmolality at the papillary tip Human Deseart rat 900 ~ 1400 mosmol/kg in maximal effect of endogenous ADH relatively long loops of Henle ~ 5000 mosmol/kg
Countercurrent multiplications UT-A1
ADH Dilute urine polyuria
원위세관 (Distal tubule) 6. 굵은오름부분 (thick ascending limb) a. Medullary thick ascending limb : 바깥수질에위치 b. Cortical thick ascending limb : 피질의수질방사에위치 7. 치밀반 (macula densa) 8. 원위곱슬세관 (distal convoluted tubule)
Distal Tubule Sodium Reabsorption Tubular Lumen (urine) Distal Tubule Epithelial Cell Capillary Lumen (blood) Na + Cl - 3 Na + ATP 2K + Ca +2 Ca-BP Cl - Ca ++ Na + Ca- ATPase
연결세관 (connecting tubule) 원위곱슬세관과피질집합관사이에위치 두 segments 의특징을공유 1. distal tubule 처럼.. - impermeable to water - active Ca 2+ reabsorption - NA + -Cl - cotransporter 에의해부분적으로 Na 흡수 2. cortical collecting tubule 처럼.. - Na + channel 에의해 Na+ 재흡수 - 알도스테론의영향으로 K 배설 4 가지세포형이섞여있다 ; 연결세관세포 (connecting tubule cell), 사이세포 (intercalated cell), 원위곱슬세포 (distal convoluted tubule cell), 및주세포 (principal cell)
집합관 (collecting duct) 연결세관 (connecting tubule, CNT) 피질집합관 (cortical collecting duct, CCD) 바깥수질집합관 (outermedullary collecting duct, OMCD) 속수질집합관 (innermedullary collecting duct, IMCD)
집합관의구성세포 Type A intercalated cells Type B intercalated cells 초반 1/3 의기시부 후반 2/3 의말단부
주세포 (principal cell) 사이세포 (intercalated cell) 밝은세포 (light cells) Na+ 흡수와 K+ 분비에관여하며, aldosterone 의영향을받는다. 항이뇨호르몬 (antidiuretic hormone, ADH) 의영향을받아수분흡수에관여한다. AQP2, AQP3, AQP4 어두운세포 (dark cells) Carbonic anhydrase 2가풍부 -> 수소이온과중탄산염을만듦 Ex> H2O + CO2 -> H + + HCO - 3 산-염기조절에관여 A형사이세포 : 수소이온배설 B형사이세포 : 중탄산염배설
Lumen Blood Na + K + ENaC + + 3Na + 2K + + ATP Aldosterone camp arginine vasopressin (AVP) H 2 O AQP 2 AQP 3 AQP 4 Principal Cell of Collecting Duct
Lumen A H 2 O + CO 2 CA II Blood H + ATP H + + HCO 3 - H + AE1 Cl - K + Aldosterone B H 2 O + CO 2 CA II Cl - Pendrin HCO 3 - + H + Cl - ATP H + Intercalated Cell of Collecting Duct
콩팥사이질 (renal interstitium) 콩팥단위와요세관사이 구성 : 사이질세포 (interstitial cell) 와세포외기질 (extracellular matrix) Cortical interstitium (7%) - fibroblasts - lymphocyte-like cells - dentritic cells (antigen-presenting cells) Medullary interstitium (20-25%) - fibroblast - lipid containing interstitial cells - dentritic cells (antigen-presenting cells)
신장의기능 Glomerular filtration 150 L/day Urine 1.5 L/day 대사노폐물배설 (urea, creatinine 등 ) 독소와약물대사물질배설수분및전해질조절소변농축산염기조절내분비기능 ( 레닌 - 안지오텐신 - 알도스테론시스템, 조혈호르몬, 비타민 D)
뇨의형성 Reabsorption Secretion Filtration Excretion
뇨의형성 1. 신혈류 (renal blood flow) - 심박출량의 20~25% 가신장으로공급 - 1.2L/min 정도의혈액이신장을통과 2. 혈액의여과 (ultrafiltration) - 뇨형성의시작 - Bulk transport of fluid from blood to kidney tubule * Isosmotic filtrate * Blood cells and proteins don t filter - 여과양 : 180 L/day - 콩팥에서단위시간당여과되는여과액의양 (ml/min) * 사구체여과율 (glomerular filtration rate, GFR) -> 콩팥기능을나타내는지표
뇨의형성 3. 신세뇨관의재흡수, 분비, 농축 - 여과액의 99% 가세뇨관을통해재흡수, 최종적으로하루 1~2L 의소변만을배설 - 근위세뇨관 (proximal tubule): 60~70% 가대량재흡수 - 헨레고리 (loop of Henle): 수분및전해질의일부가재흡수 - 원위세뇨관 (distal tubule) 및집합관 (collecting duct): 수분및전해질재흡수, 산염기조절.
Lack of adaptation of the kidney to modern diet Prehistoric humans: consumed a sodium-poor and potassium-rich diet Genetic makeup in the kidney was adapted to low Na and high K diet
Loop of Henle General mechanism of transtubular Sodium reabsorption AQP1 60-70% 5-7% Glomerulus PT DCT AQP2 TAL 20-30% CD Na + 2-3% H 2 0 1%
신장호르몬 조혈인자 (erythropoietin) - Interstitial fibroblasts (type I interstitial cell) is the major source of renal erythropoietin synthesis - 골수에서적혈구전구세포들의성장및분화를촉진 -> 혈색소생성
신장호르몬 레닌 (renin) - 사구체옆장치세포 (Juxtaglomerular apparatus) 에서합성 - 레닌 - 안지오텐신 - 알도스테론계를조절 - 나트륨균형조절, 세포외액용적조절, 혈압조절에관여 - 저혈압, 국소혈관수축, 신혈관의병리학적변화등콩팥관류가감소되는상황에서레닌분비증가
Renin-angiotensin-aldosterone system Angiotensinogen Renin from JGA Angiotensin I Converting enzyme in lung Angiotensin II Na +, H 2 O retention Blood volume Blood pressure Aldosterone
신장호르몬 25-OH-cholecalciferol (vitamin D metabolite) 이신장에서활성화된 1 α -hydroxylase 에의해수산화반응 (hydroxylation) 이일어나서 1,25-dihydroxycholecalciferol (active vitamin D) 이생성됨. 장상피에서칼슘이온흡수를촉진 뼈흡수촉진 ( 혈중칼슘과인을증가시킴 ) 부갑상선호르몬에의해합성이증가되고비타민 D 호르몬은음성되먹이기전에의해부갑상선호르몬분비를억제.
Assessment of kidney function Glomerular filtration rate (GFR) - Normal range: 90 150 ml/min - Values fall with increasing age Wesson LG. Physiology of Human Kidney 1969
Assessment of kidney function Ideal marker of GFR: - 체내에서일정한혈장농도를유지 - 사구체에서모두여과 - 세뇨관에서재흡수, 분비, 생산, 분해되지않음 - 신장을통해서만배설 Inulin: - Sugar of MW 5,000 - 가장적합한 GFR marker - 그러나생체내에서생산되지않음 ( 일정한양의정맥주사를요함 ) - Not used in clinical practice
Methods to estimate GFR Endogenous markers Exogenous markers Creatinine Inulin Serum Urinary clearance Equations Cystatin C 131 I-Iothalamate 51 Cr-EDTA 99m Tc-DTPA 크레아티닌청소율 (Ccr) = 요크레아티닌농도 (Ucr, mg/dl) X 24 시간요량 (V) 혈청크레아티닌농도 (PCr, mg/dl)
Serum creatinine 근육과 dietary meat 에서생산 간에서대사된후신장을통해서배설 사구체에서모두여과되고세뇨관에서재흡수되지않음. Minimal tubular secretion
Assessment of kidney function 요검사 (Urinalysis) - 혈색소 (occult blood) - 백혈구, 적혈구 - 단백뇨 (proteinuria) - 당뇨 (glycosuria) - 원주 (casts), 결정체 (crystals), 세균 (bacteria), etc.
Kidney damage: abnormalities of these functions
Asymptomatic urinary abnormalities ( 무증상요이상 ) Hematuria Proteinuria Tojo A, Kinugasa S Int J Nephrol (2012)
사구체성혈뇨의원인 ( 고립성혈뇨또는단백뇨동반혈뇨 ) 원발성사구체질환 - IgA 신증 (IgA nephropathy) - 얇은기저막병 (thin basement membrane disease) - 막증식성사구체신염 - 기타메산지움증식성사구체신염 (other mesangial proliferative glomerulonephritis) 전신질환및유전성질환 - 전신성홍반성루프스 - Henoch-Schonlein 자반증 - 연쇄구군후사구체신염, 기타감염후사구체신염 - 알포트증후군 (Alport syndrome) - Fabry 병 - 겸상혈구병 (sickle cell disease)
비사구체성혈뇨의원인 감염 : 방광염, 신우염, 요도염, 전립선염, 신장결핵 종양 : 방광, 요도, 전립선, 신장 결석 : 신장, 방광 신질환 : 다낭신, 신수질남성질환, 수질성해면신, 측복부동통성 - 혈뇨증후군 (loin pain-hematuria syndrome) 신혈관기형, 동맥류, Nutcracker 증후군 출혈성질환및항응고제복용 외상
사구체성혈뇨 RBC casts Dysmorphic RBC: acanthocytes 이형성적혈구 : 유극적혈구
단백뇨의원인 기능성단백뇨 (functional proteinuria) : transient 고립성단백뇨 (isolated proteinuria) - 발열 - 심한운동 / 경련 - 정신적긴장 - 임신 - 기립성단백뇨 - 국소성분절성사구체경화증 - 막성신병증 - IgA 신병증 - 당뇨병 - 아밀로이드증
단백뇨의원인 세뇨관성단백뇨 - 세뇨관의단백질흡수장애 - 간질성신염 - 항생제, 진통제, 중금속중독 과여과단백뇨 - 비정상적단백질의과잉생산에의한사구체여과증가 - Bence Jones 단백뇨 - 마이오글로빈뇨
급성신염증후군 (acute nephritic syndrome) 급성으로발생하는혈뇨, 단백뇨와함께사구체여과율감소 -> 핍뇨, 부종, 고혈압일으킴 대부분 2~3 주후신기능회복 가장흔한원인 : 연쇄구균후사구체신염 그외 IgA 신증, 막증식성사구체신염, 루프스성신염..
Normal glomerulus Poststreptococal glomerulonephritis; Low-power LM PSGN; high-power LM PSGN; EM subepithelial deposit
급속진행성사구체신염 (rapidly progressive glomerulonephritis) 급성사구체신염의일부에서신기능장애가지속적으로진행되어수주또는수개월내에말기신부전증으로이행 원인 : 항기저막병 (anti-gbm disease), 면역복합체매개사구체신염 (IC mediated GN), 극소면역성사구체신염 (pauci-immune GN)
High-power LM: hypercellular circumferential crescent ( 반월상 ) High-power LM: active hypercellular crescent containing fibrin
신증후군 (nephrotic syndrome) 심한단백뇨 (24 시간요단백 > 3.5g), 저알부민혈증, 전신부종, 고지혈증등을동반하는임상증후군. 원인 : 미세변화신질환 (minimal change disease) 막성사구체신염 (membranous nephropathy) 막증식성사구체신염 (membranoproliferative GN) 초점성국소성사구체경화증 (focal segmental glomerulosclerosis) 루프스 (lupus) 아밀로이드증 (amyloidosis)
Normal glomerulus: LM MCD: LM Normal glomerulus: EM MCD: EM
부종 (Edema) 원인 - 모세혈관혈역학의변동으로혈관에서간질로체액이동 ( 저알부민혈증, 모세혈관투과성증가, 모세혈관정수압증가등 ) - 신장에의한 sodium 과 water 저류 -> target of therapy: renal tubules
Loop of Henle: Loop diuretics Tubular Lumen (urine) Ascending Thick Limb of the Loop of Henle epithelial cell Capillary Lumen (blood) Na + ATP 2K + 2 Cl - 3 Na + K + recycling K + + K + ROMK channel Cl - - Na + Ca +2 Mg +2 Paracellular Pathway
Distal tubule: Thiazide diuretics Tubular Lumen (urine) Distal Tubule Epithelial Cell Capillary Lumen (blood) Na + Cl - 3 Na + ATP 2K + Ca +2 Ca-BP Cl - Ca ++ Na + Ca- ATPase
Collecting duct: ENaC blocker & aldosterone antagonist Lumen Blood Na + K + ENaC + + 3Na + 2K + + ATP Aldosterone camp arginine vasopressin (AVP) H 2 O AQP 2 AQP 3 AQP 4 Principal Cell of Collecting Duct
급성신부전 여러가지원인으로신기능이수시간, 수일, 또는수주내에급격히감소하는신질환. 원인 1 전신성 (Prerenal): 30% Sudden and severe drop in blood pressure (shock) or interruption of blood flow to the kidneys from severe injury or illness 2 내인성 (Intrinsic): 60% Direct damage to the kidneys by infection, inflammation, toxins, drugs, or reduced blood supply ( 신혈관성, 사구체성, 세뇨관간질성 ) 3 신후성 (postrenal): 10% Sudden obstruction of urine flow due to enlarged prostate, kidney stones, bladder tumor, or injury
Pathophysiology of Prerenal AKI
Chronic ischemic injury 급성세뇨관괴사 (acute tubular necrosis) Focal loss of tubular epithelial cells (arrows) & partial occlusion of tubular lumens by cellular debris (D)
Chronic injury Chronic hypertension Chronic glomerulonephritis Chronic tubulointerstitial fibrosis
Chronic kidney disease Nephron loss End stage renal disease
35 세의안정적인만성콩팥병환자 BUN 35 mg/dl, creatinine 2.2 mg/dl GFR 34.1 ml/min/1.73m 2 다음지표들의변화는 ( 증가, 감소, 변화없음 )? 1. 요량 2. 혈청 Na 농도 3. 혈청 K 농도 Adaptation
Adaptation GFR 120 ml/min -> 34 ml/min -> functioning nephron number가 about 2 million -> 400,000 (Despite a loss of 80% of his nephrons, the patient is barely symptomatic.) Intact nephron hypothesis As CKD advances, kidney function is supported by a diminishing pool of functioning (or hyper-functioning) nephrons, rather than a relatively constant number of nephrons each with diminished function.
Adaptation Urine volume vs Osmotic load Urine volume (L/day) = Osmotic load (mosmol/day) / Urine osmolarity (mosmol/l) Ex> Daily osmotic load: 600 mosmol 1. Maximal urine osmolarity: 1,200 mosmol/l urine volume: 600 / 1200 = 0.5 L/day 2. Isotonic urine osmolarity: 300 mosmol/l urine volume: 600 / 300 = 2 L/day
Adaptation of water excretion to nephron loss Nocturia, water excess 1. 등장뇨 (isosthenuria): AVP resistance, < 25% of normal GFR - UV : 600 mosmol/day / 300 mosmol/l = 2L/day 2. Increased osmotic load per nephron
Excretion and adaptation of major solutes Sodium (Na + ) If Na + intake remains constant, Na + excretion / residual nephron ( 즉, GFR -> the fractional excretion of sodium ) Proximal tubular reabsorption is not suppressed The reduction in reabsorption in the distal nephron (the collecting duct) Aldosterone is not suppressed Atrial natriuretic peptide (ANP): major regulatory role in tubular adaptation -> suppress tubular sodium reabsorption -> natriuresis ( 나트륨뇨배설항진 )
Excretion and adaptation of major solutes Potassium (K + ) K + excretion / residual nephron Increased secretion in the collecting tubule/duct (increased activity of the Na + -K + ATPase on basolateral surface of principal cells); aldosterone Increased K excretion at colon: aldosterone ( 정상인 10%, CKD 30~50%) Decreased K reabsorption at Henle s loop
Excretion and adaptation of major solutes Hydrogen ion (H + ) 1. Metabolic acidosis 1) decreased acid excretion in collecting duct (intercalated A cell) 2) defective HCO3 - reabsorption 3) organic acid (sulfates, urates, phosphates) retention 2. Adaptation 1) increased urine ammonium/nephron (4배); stage 2-3 2) buffering of acid at bone: bone change (loss of calcium; renal osteodystrophy)
Mineral metabolism: calcium, phosphate, and parathyroid Hormone Abnormalities in mineral metabolism - Decreased phosphate excretion - Decreased hydroxylation of vitamin D
A summary of renal function
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