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1 Renal Failure and Uremia Part I Shen J Department of Pathophysiology, Zhejiang University School of Medicine

2 Introduction Acute renal failure Chronic renal failure Uremia 2

3 Review of normal renal function Excretion filtration, resorption and secretion, to maintain the balance in water, electrolytes, acid and alkali Endocrine renin, prostaglandin, erythropoietin (EPO), 1,25 (OH) 2 VitD 3 Inactivation PTH, gastrin 3

4 Vitamin D metabolism 25-hydroxylase 1-alpha-hydroxylase J Crohns Colitis May;6(4):

5 (nephron) 5

7 Concept of renal failure Renal failure is a condition in which the kidneys fail to remove metabolic end-products from the blood and regulate the fluid, electrolyte, and ph balance of the extracellular fluids. Excretion function, leadingto: accumulation of metabolic end-products disorders of fluid & electrolyte, acid-base balance endocrine disorders Renal insufficiency 7

8 Etiology( 病因 ) Kidney (renal) disease Other systems and systemic disease Manifestation of renal dysfunction ( 主要表现及发生机制 ) Glomerular dysfunction Tubular dysfunction 泌尿功能障碍 Endocrine disorder 内分泌功能障碍 8

梗阻间质水肿 Renal blood flow πgc 上升速度 Glomerular capillary filtration coefficient

9 Manifestation of renal dysfunction Glomerular dysfunction Factors affecting Glomerular Filtration Rate (GFR) Net filtration pressure (NFP) P GC 全身心肾 P BS 梗阻间质水肿 Renal blood flow πgc 上升速度 Glomerular capillary filtration coefficient (Kf) -- permeability of the filtration membrane -- total surface area for filtration

Manifestation of renal dysfunction Tubular dysfunction Proximal tubule Renal glycosuria, aminoaciduria, phosphaturia, renal tubular acidosis (HCO 3- ) ( 近端肾小管性酸中毒 ) Medullary loop Hypotonic or

10 Manifestation of renal dysfunction Tubular dysfunction Proximal tubule Renal glycosuria, aminoaciduria, phosphaturia, renal tubular acidosis (HCO 3- ) ( 近端肾小管性酸中毒 ) Medullary loop Hypotonic or isotonic urine, polyuria Distal tubule; collecting duct Na + K + 代谢障碍 (hypona, hyperk); acid-base disorder( 泌 H + 排 NH + 4 重吸收 HCO 3- ); polyuria; Endocrine disorder Renin (RAS) EPO 1,25 (OH) 2 VitD 3 PTH hypertension anemia renal osteodystrophy others 10

11 Classification of renal failure Acute Renal Failure 较常见, 凶险, 多可逆 The kidneys abruptly stop working Chronic Renal Failure 隐匿, 不可逆 The kidneys lose their functions gradually 11

12 Acute Renal Failure, ARF

13 Definition Etiology & classification Prerenal failure Intrinsic renal failure Post(obstructive) renal failure Pathogenesis Clinical manifestation Therapy 13

14 Definition Acute renal failure (ARF) is defined as a precipitous and significant (>50%) decrease in glomerular filtration rate (GFR) over a period of hours to days, with an accompanying accumulation of nitrogenous wastes in the body. 14

15 急性肾功能衰竭的定义急性肾功能衰竭 (acute renal failure,arf) 是指各种病因引起双侧肾脏在短期内 ( 泌尿 ) 功能急剧降低, 导致机体内环境出现严重紊乱的病理过程和临床综合症肾泌尿功能障碍表现为 GFR 迅速下降, 出现少尿无尿 ; 内环境紊乱主要表现为氮质血症高钾血症和代谢性酸中毒急性肾功能衰竭根据尿量减少与否, 分为少尿型 ( 成人每日尿量少于 400ml) 和非少尿型 ( 成人每日尿量大于 400ml) 两种类型急性肾衰病情凶险, 临床较常见, 但若及时诊治, 预后较好 15

16 Etiology 病因 Pre-renal 肾前性 - decreased renal perfusion - functional RF 功能性 Intrinsic-renal 肾性 - injury to or malformation of kidney tissues. ATN (acute tubular necrosis): 缺血 ; 中毒 - parenchymal RF 器质性 Post-renal (<5%) 肾后性 - obstruction of urinary flow between the kidney and urinary meatus. - obstructive RF 阻塞性 16

17 Prerenal failure - diseases that compromise renal perfusion P GC 全身心肾 Decreased effective arterial blood volume - hypovolemia, CHF, liver failure, sepsis Renal arterial disease - renal arterial stenosis (atherosclerotic, fibromuscular dysplasia), embolic disease (septic, cholesterol) 尿液性质 : 尿比重, 尿钠 17

18 Intrinsic renal failure - diseases of the renal parenchyma, specifically involving the renal tubules, glomeruli, interstitium ATN, ischemia, toxins (eg, aminoglycosides, radiocontrast, cisplatin, ethylene glycol) Interstitial diseases - acute interstitial nephritis, drug reactions, autoimmune diseases (eg, systemic lupus erythematosus [SLE]), infiltrative diseases (sarcoidosis, lymphoma), infectious diseases (Legionnaire disease, hantavirus) Acute glomerulonephritis Vascular diseases - hypertensive crisis, polyarteritis nodosa, vasculitis 尿液性质 : 尿比重低, 常固定 ( 等渗尿 ), 尿钠 18

19 Postrenal failure - diseases causing urinary obstruction from the level of the renal tubules to the urethra Tubular obstruction from crystals (eg, uric acid, calcium oxalate, acyclovir 阿昔洛韦, sulfonamide 磺胺类, methotrexate, myeloma light chains) Urethral obstruction - benign prostatic hypertrophy; prostate, cervical, bladder, colorectal carcinoma; bladder hematoma; bladder stone; obstructed Foley catheter; neurogenic bladder. 19

20 Pathogenesis 发病机制急性肾衰发病机制的中心环节是 GFR 的降低 Renal ischemia 肾缺血 Obstruction of renal tubules 肾小管阻塞 Urinary reflux 原尿返流 Cell damage 细胞损伤 20

21 Pathogenesis 发病机制急性肾衰发病机制的中心环节是 GFR 的降低 Renal ischemia 肾缺血 Obstruction of renal tubules 肾小管阻塞 Urinary reflux 原尿返流 Cell damage 细胞损伤 21

22 Renal ischemia 肾缺血 ARF 初期主要发病机制 1. 肾灌注压降低 (decrease in renal perfusion pressure) 2. 肾血管收缩 (contraction of renal vessels) 3. 肾脏血液流变学的变化 (alteration of renal hemorheology) 22

23 1. 肾灌注压降低 BP 80~180 mmhg BP<80 mmhg 肾血管舒张或收缩肾血管收缩肾血流自身调节肾血流失去自身调节 RBF & GFR 不变 RBF & GFR 降低 23

24 Renal ischemia 肾缺血 1. 肾灌注压降低 (decrease in renal perfusion pressure) 2. 肾血管收缩 (contraction of renal vessels) 缩血管 : 儿茶酚胺,RAS, 内皮素 (ET) 扩血管 : 前列腺素,ANP,NO 3. 肾脏血液流变学的变化 (alteration of renal hemorheology) 24

25 儿茶酚胺 PLC pathway From wikipedia 25

26 AngII, ET-1 Gq:Phospholipase C (PLC) pathway Gq PLC 二酰基甘油 (DAG) PKC 调控基因表达三磷酸肌醇 (IP3) 26

27 Renal ischemia 肾缺血 1. 肾灌注压降低 (decrease in renal perfusion pressure) 2. 肾血管收缩 (contraction of renal vessels) 缩血管 : 儿茶酚胺,RAS, 内皮素 (ET) 扩血管 : 前列腺素,ANP,NO 3. 肾脏血液流变学的变化 (alteration of renal hemorheology) 27

28 PKG 钙离子内流外流 28

29 Renal ischemia 肾缺血 1. 肾灌注压降低 (decrease in renal perfusion pressure) 2. 肾血管收缩 (contraction of renal vessels) 缩血管 : 儿茶酚胺,RAS, 内皮素 (ET) 扩血管 : 前列腺素,ANP,NO 3. 肾脏血液流变学的变化 -- 进一步加剧肾缺血 (alteration of renal hemorheology) 29

30 3. Alteration of renal hemorheology Blood viscosity Capillary occlusion: WBC Blood resistance RBF Capillary spasm, thickening 30

31 Pathogenesis 发病机制急性肾衰发病机制的中心环节是 GFR 的降低 Renal ischemia 肾缺血 Obstruction of renal tubules 肾小管阻塞 Urinary reflux 原尿返流 Cell damage 细胞损伤 31

32 Ischemia, toxins Obstruction of renal tubules 肾小管阻塞 Hemolytic uremic syndrome Crush syndrome Drug crystal ATN Hb, Mb Cell debris Cast Obstruction of renal tubules Ureteral obstruction PBS Oliguria GFR 32

33 Pathogenesis 发病机制急性肾衰发病机制的中心环节是 GFR 的降低 Renal ischemia 肾缺血 Obstruction of renal tubules 肾小管阻塞 Urinary reflux 原尿返流 Cell damage 细胞损伤 33

34 Urinary reflux 原尿返流 Tubular necrosis Base membrane breaks Urine renal interstitium Interstitial edema Oliguria Obstruction of renal tubules Obstruction of renal capillary 34

35 尿液肾小管基底膜剥脱肾小管细胞受损坏死细胞及碎片阻塞肾小管阻塞及原尿返流示意图 35

36 Pathogenesis 发病机制急性肾衰发病机制的中心环节是 GFR 的降低 Renal ischemia 肾缺血 Obstruction of renal tubules 肾小管阻塞 Urinary reflux 原尿返流 Cell damage 细胞损伤 36

37 Cell damage 细胞损伤肾小管阻塞和原尿返漏的主要原因 : 肾小管上皮细胞功能异常 1. ATP deficiency major Ischemia, oxygen deficiency ATP production hydrolysis ; Lasting oxygen deficiency mitochondria damage ATP 2. Cell Swelling ATP Na + -K + -ATPase activity ; cytoskeleton damage 3. Calcium overload 钙超载 ATP Na + -Ca 2+ activity ; ER calcium pump activity Ca 2+ 37

38 Cell damage 细胞损伤 Ca 2+ 刺激线粒体钙泵摄钙, 形成不溶性磷酸钙, 干扰氧化磷酸化,ATP Ca 2+ 蛋白酶激活促氧自由基生成细胞损伤 Ca 2+ 磷脂酶激活膜性结构受损 4. Oxygen free radical 氧自由基 lipid peroxidation of membrane protein denaturalization DNA disruption 38

39 急性肾功能衰竭发病机制肾毒素血液流变学变化有效循环血量肾小管细胞损伤急性肾小管坏死器质性血粘度白细胞阻塞微血管微血管变化肾灌注压儿茶酚胺髓袢升支粗段损伤 Na +, Cl - 重吸收各种管型形成肾小管阻塞上皮细胞坏死, 基底膜断裂原尿返流 RAS 肾血管收缩 RAS 管腔内压间质水肿舒血管物质 (PG 等 ) 有效滤过压压迫肾小管压迫毛细血管肾缺血 GFR 血流泌尿障碍, 内环境紊乱 ARF 39

40 Renal vascular system Q: Why ischemic damage is more severe in cortex and outer zone of medulla in ATN? 40

41 Q: Why nephron toxins preferentially damage the proximal tubules? 41

42 Characteristics & clinical courses 少尿型 ARF 分三个阶段 : Oliguric phase 少尿期 Diuretic phase 多尿期 Recovery phase 恢复期 42

43 Oliguric phase 少尿期 Usually lasting for 1 to 6 weeks,the average duration is between 7 & 10 days. 此期越长预后越差 Features of urine: I. Oliguria or Anuria II. Hematuria and casts Azotemia 器质性 III. Low specific gravity and osmolality IV. Urinary [Na + ] above 20mM creatinine, uric acid nitrogen, urea, BUN 定义 : 由于肾小球滤过率下降, 含氮的代谢终产物如尿素尿酸肌酐等在体内蓄积, 因而血中非蛋白氮 (nonprotein nitrogen, NPN) 的含量增加 ( > 28.6mmol/L, >40mg/dL) 即血液中非蛋白含氮物质增多称氮质血症机制 : a. excretion b. catabolism production 43

44 Oliguric phase 少尿期 Metabolic acidosis Catabolism acidic products Acid excretion Secretion of ammonia and hydrogen Water intoxication GFR H 2 O excretion GFR ADH secretion Catabolism endogenous water Transfer of Na+ from extracellular to intracellular Diluted hypona Edema/water intoxication 44

45 Oliguric phase Hyperkalemia severest 两周内死亡的最主要原因 Oliguria K + excretion Transfer of K + from intracellular to extracellular (catabolism, acidosis) Distal tubular Na + -K + exchange (hypona) 45

46 尿液性质尿比重尿渗透压尿钠尿肌酐 / 血肌酐尿常规 RFI 肾衰指数尿钠 /( 尿肌酐 / 血肌酐 ) FENa 钠排泄分数功能性肾衰和器质性肾衰 (ATN) 的鉴别 ( 尿钠 / 血钠 )/( 尿肌酐 / 血肌酐 )*100% 治疗与反应功能性肾衰器质性肾衰 >1.020 <1.015 >500mOsm/L <400mOsm/L <20mmol/L >40mmol/L >40 <20 正常蛋白尿管型红细胞白细胞 <1 >2 <1 % >2% 应迅速补充血容量使肾血流恢复,GFR 需严格控制补液量量出而入补液后尿量迅速增多尿量持续减少病情明显好转甚至使病情恶化 46

47 Red Cell Cast 47

48 White Cell Casts 48

49 Diuretic phase 多尿期 urine > 400ml/day, 1-2 weeks. Mechanisms of diuresis: Non-integrated function of palingenetic tubules Cumulation of urea during oliguria phase (leads to osmotic diuresis) Relieve of the tubular obstruction Caution: BUN,Pcr> Normal Fluid and electrolyte abnormalities 49

50 Recovery phase 恢复期 Fully recovery of renal function takes several weeks (most typically) to a year, characterized by healing of tubular epithelial cells; The mortality associated with ATN is ~50%, the deaths are related to the condition causing renal failure or infections. 50

51 Nonoliguric acute renal failure 非少尿型 ARF 近年有增多趋势 ; 可能与病人医疗意识加强医疗诊治手段提高及肾毒性抗生素广泛应用有关机制 :1 不同肾单位受损程度不一, 小部分肾单位的肾血流量和肾小球滤过功能存在 ;2 肾小管重吸收功能障碍远较肾小球滤过功能降低为重 ;3 肾髓质形成高渗状态的能力降低, 使尿液浓缩功能下降, 故发病后尿量无明显降低, 在 400~1000 ml/d 左右非少尿型 ARF 较少尿型 ARF 病情轻预后好, 但因症状轻而不太明显, 容易延误病人的就诊或引起医生的漏诊非少尿型 ARF 不及时治疗, 则会转化为少尿型 ARF 51

52 Management Treatment of the original diseases Treatment against symptoms Correct hyperkalemia, acidosis and azotemia Dialysis is strongly recommended 52

53 Dialysis indications I. Serum abnormalities unresponsive to medical therapy a. Severe acidosis b. Severe hyperkalemia II. Uremia a. Mental status changes (usually delirium) b. Nausea and vomiting c. Pericarditis (pericardial friction rub) III. Volume overload 53

54 Peritoneal Dialysis 54

55 Hemodialysis Blood is circulated through artificial cellophane membrane that permits a similar passage of water and solutes 55

56 case 某 8 岁患儿因感染采用磺胺嘧啶治疗, 因使用剂量过大, 用药 5 天后, 连续 3 日尿量少于 100ml/d, 急诊入院经查 : 血肌酐 480μmol/L( 正常值为 <178μmol/L), 尿钠 100mmol/L( 正常值为 <20mmol/L), 尿相对密度问: 该病人是否发生了肾功能衰竭? 如果是, 是急性肾功能衰竭, 还是慢性肾功能衰竭? 是功能性的还是器质性的? 该病人的尿少是肾前性因素肾性因素还是肾后性因素所致, 产生机制是什么? 为什么血肌酐尿钠浓度增高? 为什么尿相对密度降低? 56

肾功能不全

肾功能不全肾功能衰竭和尿毒症 ( 一 ) Renal Failure and Uremia 沈静 Tel: 88208210 E-mail: offosj@yahoo.com.cn Department of Pathophysiology,, Zhejiang University School of Medicine 1 Introduction 2 Acute renal failure 3 Chronic