肾功能不全

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1 肾功能衰竭和尿毒症 ( 二 ) Renal Failure and Uremia 沈静 Tel: offosj@yahoo.com.cn Department of Pathophysiology,, Zhejiang University School of Medicine

2 1 Introduction 2 Acute renal failure 3 Chronic renal failure 4 Uremia 2

3 Chronic Renal Failure, CRF

4 Definition Etiology Pathogenesis Clinical manifestation Therapy 4

5 Definition It is a process that the kidneys are affected progressively by the insults and thus an irreversible loss of large numbers of functioning nephrons occurs. 功能性肾单位数目 Resultant retention of nitrogenous solutes, derangements of fluid, electrolyte and acid-base balance, and failure of hormone production. Endocrine Disorder 5

6 Serious clinical symptoms often do not occur until the number of functional nephrons falls to at least 70 percent below normal. Normal blood concentrations of most electrolytes and normal body fluid volumes can still be maintained until the number of functioning nephrons decreases below percent of normal. 因为肾组织的破坏是逐渐发生的, 而且肾脏又有较强的代偿能力, 故慢性肾衰常常是缓慢发展, 病程迁延数月数年以至更长的时间, 最后常导致尿毒症而死亡 6

7 Causes of CRF Any disorder that permanently destroys nephrons can result in chronic renal failure. 我国 : 慢性肾小球肾炎最常见 (50%~60%) 西方 : 糖尿病肾病首位 (1) 肾脏疾患 : 慢性肾小球肾炎慢性肾盂肾炎肾结肾肿瘤全身性红斑狼疮原发性 (2) 肾血管疾患 : 高血压肾小动脉硬化等 (3) 尿路慢性梗阻 : 尿路结石前列腺肥大等 (4) 全身代谢性疾病 : 糖尿病肾病等继发性 (5) 其他 : 药物性肾损伤等 7

8 Clinical courses of CRF 内生肌酐清除率 Ccr: 较好反映肾排泄功能的指标肌酐是体内肌酸经脱水反应形成血中肌酐分内外源性两种, 内源性为主, 来自肌肉代谢 ; 外源性来自肉类食物的代谢饮食条件和肉活动相对稳定时, 血肌酐与体内肌肉总量关系密切, 受饮食影响较肌酐是小分子物质, 释放到血液中, 随尿排泄可通过肾小球滤过, 在肾小管内很少吸收, 每日体内产生的肌酐, 几乎全部随尿排一般不受尿量影响 8

9 Ccr 公式 : creatinine clearance rate: [Ucr] * V/min (ml/min) [Pcr] * 公式的校正 : 年龄体重性别体表面积等 * 正常值 :80-120ml/min * 无肌酐饮食 2-3 天后测定 * 无肌酐饮食 : 摄入蛋白质 <40g/ 天, 禁肉食, 避免剧烈运动 9

10 慢性肾功能衰竭的发展过程和分期内生肌酐清除率氮质血症临床表现 ( 与正常值比 ) 代偿期 >30% 无无任何症状但不能负荷额外的水电解质和酸碱失代偿期肾功能不全期 <20-30% 轻中度轻度消化道症状 (Renal Insufficiency) 贫血多尿夜尿肾功能衰竭期 <20-25% 较重明显多尿夜尿和水 (Renal Failure) 电解质酸碱紊乱尿毒症期 <10% 严重全身中毒症状明显, (Uremia; End-Stage Renal Disease, ESRD) 各脏器系统功能障碍 10

11 Pathogenesis 发病机制 Intact nephron hypothesis 健存肾单位假说 Glomerular hyperfiltration hypothesis 肾小球过度滤过假说 Trade-off hypothesis 矫枉失衡假说 Tubular and interstitial injury 肾小管肾间质损害 Lipid metabolism disorder 脂质代谢紊乱 11

12 1. Intact nephron hypothesis 健存肾单位假说健存肾单位进行性减少数目 2. Glomerular hyperfiltration hypothesis 肾小球过度滤过假说健存肾单位高灌注高滤过 Adaptation mechanism: 长期 : 引起肾小球肥大增生甚至硬化 Nephron destroyed the remaining counterparts adapt by increasing GFR, tubular resorption and excretion. When the intact nephron is decreasing to a certain degree, it goes to non-compensatory stage CRF 12

13 3. Trade-off hypothesis 矫枉失衡假说 VitD3 FGF-23 13

14 (Na-Pi 共转运体 ) (MAPK pathway PTH mrna ) From Nephrol. Dial. Transplant. (2010) 25 (5):

15 4. Tubular and interstitial injury 肾小管肾间质损害与肾小球病变比, 与 CRF 的结局更相关适应性肾小管高代谢率蛋白尿的毒性作用氧自由基损害原发性或继发性肾间质疾病 Normal: tubular creatinine excretion < 10% 肥大增生变性坏死 RF: may increase to 30% 管型, 原尿返流, 炎症反应生成中和及清除失去平衡肾小管萎缩, 肾纤维化 15

16 5. Lipid metabolism disorder 脂质代谢紊乱脂质沉积影响细胞间信号传递, 刺激系膜增生和细胞外基质积聚, 分泌大量炎症介质和细胞因子, 吸引炎症细胞趋化和聚集脂质过氧化自由基增多损害肾小管和间质细胞 16

17 Clinical manifestations of CRF I. Disorders in urinary system 泌尿功能障碍 Urine: from polyuria, nocturia to oliguria Urine osmolarity: hyposthenuria and isosthenuria Microscopic urinalysis: proteinuria, hematuria, pyuria and different type of casts 17

18 慢性肾衰髓襻功能受损多数肾单位被破坏尿液浓缩障碍健存肾单位血流原尿溶质原尿流速渗透性利尿重吸收多尿 18

19 早期 : 浓缩障碍, 稀释正常低渗尿低比重尿晚期 : 浓缩, 稀释均障碍等渗尿 19

20 II. Changes in homeostasis (1) Azotemia GFR Cumulation of NPN NPN>40mg/dl BUN P Cr : 与肾功能损害不平行 [Ucr] * V/min C Cr : 灵敏反映 GFR 变化 [Pcr] 体内毒素堆积造成尿毒症的主要因素一过性氮质血症 20

21 (2) Acidosis AG=Na + -(HCO 3- +CL - ) Early stage of CRF Secretion of H + and resorption of HCO 3 - Compensatory resorption Cl - from intestinal 排酸保碱障碍 CRF 早期,GFR>25%, HPO 4 2-,SO 4 2- 排泄正常 Acidosis with normal AG Late stage of CRF Excretion of nonvolatile acid, such as sulphate phosphate Acidosis with high AG Secretion of NH 4 + 早期 : 轻度代酸可无症状 ; 晚期 ( 尤其尿毒症 ) 呼吸加深加快, 甚至昏迷 21

22 阴离子间隙 (AG anion gap) AG: 血浆中未测定的阴离子和未测定的阳离子的差值 AG=Na + -(HCO 3 - +CL - ) 正常值范围 :10~14mmol/L 反映血浆中固定酸含量的指标 AG 一定有代酸, 代酸不一定有 AG 代酸分两类 : AG 正常型 ( 高血氯 ) AG 增大型 ( 血氯正常 ) 22

23 (3) Disorders in electrolytes metabolism Sodium: 调节能力下降 salt lossy kidney 失盐性肾 :hyponatraemia 毒素抑制, 醛固酮反应 polyuria, resorption 晚期 CRF: hypernatraemia 钠水丢失, 无力, 低血压, 休克 secretion 钠水潴留, 水肿, 高血压, 心衰 Severe hyponatraemia may jeopardize life of patients, therapeutic supplementation of salt may embitter renal hypertension Conflict in therapy 23

24 Potassium: normal, hyperkalemia or hypokalemia 早期 : 一般能维持正常醛固酮排 K + 肠道排 K + Excretion of K + during CRF depends on the volume of urine 晚期 : 尿毒症, 少尿 If the quantum of urine is adequate, plasma level of K + could be maintained normal Hyper- Hypo- Gastrointestinal: 摄入不足, 丢失 Transfer of K + from extracellular to intracellular ( 继发性醛固酮代碱 ) Drug: diuretic Oliguria, K + excretion Transfer of K + from intracellular to extracellular (catabolism, 代酸 ) Drug: interfere with RAAS 24

25 Calcium and phosphorus: Hypocalcemia Hyperphosphatemia Renal osteodystrophy Trade-off hypothesis 矫枉失衡假说 25

26 III. Renal hypertension 肾性高血压晚期 CRF 肾脏疾病 GFR 肾血液灌流量肾实质破坏钠水排出肾素分泌 Ouabain 哇巴因 ( 乌本苷 ) 钠水潴留 Ald 血管紧张素 II 血容量心输出量反射性血管收缩血管壁增厚外周阻力高血压肾髓质细胞 PGA2 PGE2 生成 26

Ouabain Hypervolemia promotes the release of ouabain, which increases vascular smooth muscle tone through the inhibition of Na + /K + -ATPase and the

27 Ouabain Hypervolemia promotes the release of ouabain, which increases vascular smooth muscle tone through the inhibition of Na + /K + -ATPase and the subsequent increase in intracellular Na + concentration, reversal of the 3Na + /Ca 2+ exchanger, and a rise in cytosolic Ca 2+ concentration. Nature 415, ,

28 III. Renal hypertension 肾性高血压 Renal ischemia 28

29 III. Renal hypertension 肾性高血压晚期 CRF 肾脏疾病 GFR 肾血液灌流量肾实质破坏钠水排出肾素分泌钠水潴留 Ald 血管紧张素 II 血容量心输出量反射性血管收缩血管壁增厚外周阻力高血压肾髓质细胞 PGA2 PGE2 生成 29

30 钠水潴留 : 钠依赖性高血压单纯用降压药效果不佳, 应首先清除多余的钠水 ( 限制钠盐摄入和用利尿剂 ) RAAS: 肾素依赖性高血压不宜限制钠盐摄入和用利尿剂 ; 应选择抗 RAS 药物 ( 血管紧张素转换酶抑制剂 ) 30

31 IV. Renal anemia 肾性贫血 - EPO production 重要原因 - EPO function 毒素抑制骨髓对 EPO 的反应 - RBC life ATP 减少, 毒素 - Iron deficiency hemodialysis; anorexia; dietary restriction - Hemorrhagic tendency V. Hemorrhagic tendency 出血倾向 Abnormality in platelet function 31

32 VI. Renal osteodystrophy 肾性骨营养不良 See Trade-off hypothesis 慢性肾功能衰竭 1,25-(OH) 2 VitD 3 GFR 肠钙吸收排磷低钙血症高磷血症酸中毒骨质钙化障碍 PTH 分泌骨盐溶解骨质脱钙肾性骨营养不良 32

33 Metastatic calcification Hyperparathyroidism 33

34 Management 早中期 CRF Treatment of the original diseases Treatment against symptoms Correct hyperkalemia, acidosis and azotemia 34

35 Uremia 尿毒症

36 Uremia Is the common end-stage for ARF and CRF 尿毒症是指急慢性肾功能衰竭最危重的阶段终末阶段 It is a syndrome characterized by Cumulation of metabolites and endogenous toxins, Imbalance in water, electrolytes, acid-base metabolism Deregulation in endocrine system 自体中毒 36

37 Pathogenesis 发病机制甲状旁腺激素 (parathyroid hormone, PTH) 胍类化合物 (guanidine compound) 尿素 (urea) 胺类 (amines) 中分子物质 (mid-molecular materials) 37

38 Clinical Manifestations Neurological disorders: 脑病 : 疲乏头晕头痛记忆力减退睡眠障碍, 注意力不集中情感淡漠语言减少定向障碍抑郁谵妄幻觉昏迷手足搐搦肌痉挛甚至癫痫样发作毒素使 Na + K + -ATP 酶活性脑细胞内钠含量脑水肿肾性高血压脑血管痉挛缺氧, 毛细血管通透性增高神经细胞变性, 脑水肿周围神经病变 : 进展缓慢远端对称的感觉 - 运动神经病变, 下肢多见, 晚期可见肌无力深反射迟钝消失胍基琥珀酸抑制神经细胞中的转酮醇酶髓鞘发生变性 38

39 Clinical Manifestations Gastrointestinal disorders: Anorexia, nausea, vomiting, gastroenteritis, GI bleeding, peptic ulcer. 唾液带氨味消化道排出尿素增多, 经尿素酶分解生成氨, 刺激胃粘膜产生炎症以至溃疡发生 ; 胃泌素灭活 Cardiovascular disorders: Pericarditis, hypertension, congestive heart failure, coronary artery disease, myocardiopathy. Hematologic disorders: Anemia, bleeding tendency due in part to platelet dysfunction. Immune system disorders: 60% patients 细胞免疫反应明显受到抑制, 体液免疫反应正常或稍减弱机制可能是毒素抑制了淋巴细胞分化和成熟, 减弱了中性粒细胞的吞噬和杀菌能力 39

40 Pulmonary disorders: 肺部感染, 酸中毒使呼吸加深加快, 呼吸困难, 呼吸有氨味心衰低蛋白血症肺 Cap. 通透性增加钠水潴留肺水肿尿酸刺激间质性肺炎胸膜炎磷酸钙肺内沉积肺钙化 Metabolic disorders: 糖耐量降低可能与血中存在胰岛素拮抗物使外周组织对胰岛素反应降低有关蛋白质代谢障碍由于食欲低下饮食限制毒素, 使肝脏蛋白合成减少分解增加低白蛋白血症脂肪代谢障碍常有高脂血症, 主要是血清甘油三酯增高胰岛素拮抗物质使肝合成甘油三酯增加 ; 脂蛋白酶活性降低致使甘油三酯清除率降低 40

41 Endocrine disorders: renin, prostaglandins, EPO, 1,25 (OH) 2 VitD 3, PTH sexual dysfunction and infertility Bone, calcium, phosphorus disorders: Hyperphosphatemia, hypocalcemia, tetany, metastatic calcification, secondary hyperparathyroidism, 1,25-dihydroxy vitamin D deficiency, osteomalacia, osteitis fibrosa, osteoporosis, osteosclerosis. Skin disorders: Pruritus, pigmentation, easy bruising, uremic frost 尿素霜. 与高钙血症皮肤转移性钙化及刺激皮肤肥大细胞释放组胺等有关 Fluid and electrolyte disorders: Hyponatremia, hyperkalemia, hypermagnesemia, metabolic acidosis, volume expansion or depletion 41

42 42

43 Principles of treatment for CRF & Uremia Conservative management Dialysis Peritoneal dialysis 腹膜透析 Hemodialysis 血液透析 Renal transplantation 43

44 Peritoneal dialysis 腹膜透析价格相对较低, 操作简便小儿老年人糖尿病人心血管病人出血倾向病人等用腹膜作为半渗透膜, 将配制好的透析液经导管灌入患者的腹膜腔在腹膜两侧存在溶质的浓度梯度差, 高浓度一侧的溶质向低浓度一侧移动 ( 扩散作用 ); 水分则从低渗一侧向高渗一侧移动 ( 渗透作用 ) 通过腹腔透析液不断地更换, 以达到清除体内代谢产物毒性物质及纠正水电解质平衡紊乱的目的 44

45 Peritoneal Dialysis 45

46 Hemodialysis 血液透析要建立血管通路, 比如动静脉瘘血液和透析液在透析器 ( 人工肾 ) 内借半透膜接触和浓度梯度进行物质交换, 使血液中的代谢废物和过多的电解质向透析液移动, 透析液中的钙离子碱基等向血液中移动清除患者血液中的代谢废物和毒物 ; 调整水和电解质平衡 ; 调整酸碱平衡具有人体肾脏的部分功能 ( 但不能替代肾脏的内分泌和新陈代谢功能 ) 46

47 Hemodialysis Blood is circulated through artificial cellophane membrane that permits a similar passage of water and solutes 47

48 Principles of treatment for CRF & Uremia Conservative management Dialysis Peritoneal dialysis Hemodialysis Renal transplantation 48

49 case 患者, 女,35 岁患肾小球肾炎反复浮肿 20 年, 尿闭 1 天急诊入院患肾炎后反复眼睑浮肿 6 年来排尿次数增多, 每天 10 余次, 夜尿 4-5 次,2000ml/ 天期间,BP146/100mmHg,Hb40-70g/L,RBC /L 尿蛋白 +,RBC WBC 上皮细胞 5-7/HP 3 年来夜尿更明显, 尿量达 ml/ 天, 比重固定在左右全身骨痛并逐渐加重, 经抗风湿及针灸无效近 10 天来尿少浮肿加重, 食欲锐减恶心呕吐腹痛全身瘙痒四肢麻木轻微抽搐一天来尿闭, 症状加重急诊入院 T37 R20 次 / 分 P120 次 / 分 BP150/100mmHg RBC /L Hb47g/L,WBC /L, 血磷 1.9mmol/L, 血钙 1.3mmol/L 尿蛋白 +, RBC10-15/Hp,WBC0-2/Hp, 上皮 0-2/Hp, 颗粒管型 2-3/LP X 线检查 : 双肺正常, 心界略扩大, 手骨质密度减低骨小梁稀疏, 骨质变薄 49

Microsoft PowerPoint - renal failure and uremia_sj_2_ ppt [兼容模式]

Microsoft PowerPoint - renal failure and uremia_sj_2_ ppt [兼容模式] Renal Failure and Uremia Part II Shen J Department of Pathophysiology, Zhejiang University School of Medicine 1 2 3 4 Introduction Acute renal failure Chronic renal failure Uremia 2 Chronic Renal Failure,