department of pathophysiology, shandong university school of medicine 薛冰 renal insufficiency
TRANSCRIPT
Department of Pathophysiology,Shandong University School of Medicine
薛冰
Renal Insufficiency
INDEX
• Acute renal failure(ARF)Acute renal failure(ARF)
• Chronic renal failure(CRF)Chronic renal failure(CRF)
Functions of the Kidney
1.Excretion1.Excretion
Remove waste product from the body ;Regulate electrolyte and acid-base balance.
2. Endocrine 2. Endocrine Produce renin 、 EPO 、 and prostaglandinsActive VitD3
Inactivate gastrin 、 PTH.
Renal insufficiency
Diseases Dysfunction of excretion and endocrine
Symptomsand signs
Edema, hypertension, oliguria, polyuri
a, proteinuria, anemia, osteodystrophy.
Causes
1. Primary renal diseasesPrimary glomerular diseases, Primary tubular diseases, Interstitial nephritis, et al.
2. Secondary renal lesionCirculatory system diseases, immunity diseases, metabolic diseases, hematopathy( 血液病) , et al.
Part I Acute Renal Failure(ARF)
• Definition
• Etiology & classification
• Pathogenesis
• Alteration of Metabolism and Function
• Prevention & Treatment
I 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.
water intoxication, azotemia, hyperkalemia, metabolic acidosis
Morbidity and mortality
• 急性肾衰竭迄今为止仍是威胁人类生命的危重病症,第二次世界大战时其死亡率高达 91% ,越南战争时期由于透析技术的应用,其死亡率降为 68% 。近年来单纯急性肾衰竭的死亡率为 7%~23% ,而复杂性急性肾衰竭的死亡率仍高达 50%~80% 。急性肾衰竭的死亡率取决于原发病的严重程度,以往的研究表明,急性肾衰竭的病因不同,其死亡率有明显差别,如缺血性原因者死亡率为 30% ,而中毒性原因者死亡率仅为 10% .
1. causes Prerenal ~~ Intrarenal ~~ Postrenal ~~
2. urine volumeOliguric ~~
(<400ml/day)
Nonoliguric ~~(>400ml/day)
3. renal lesion functional~~organic ~~
obstructive ~~
II Etiology and Classifications
Causes and classification
Pre-renal (~70% of cases)Pre-renal (~70% of cases)
functional renal failure; preren
al azotemia
Intra-renal (~25% of cases)Intra-renal (~25% of cases)
parenchymal renal failure
Post-renal (<5% of cases)Post-renal (<5% of cases)
postrenal azotemia
adrenal gland
ureter
renal pelvis
urinary bladder
Cause and classification
(I) Prerenal failure - Diseases that compromise renal perfusion
Decreased effective arterial blood volume - Hypovolemia (E
CF↓ 50% → RBF ↓ 90-95%)
Congestive heart failure (CO ↓ 40 % → RBF ↓ 72 %)
sepsis (vasodilatation)
pathogenesis of pre-renal ARF
pre-renal factors
shock caused by haemorrhage 、 infection 、 AHF 、 serious anaphylactic reaction and others (hepatorenal syndrome )
ADH effective blood volume Ald BP decrease
kidney perfusion renal blood vessel contraction
renal blood flow
Glomerular EFP
GFRGFR urine
Characteristics of prerenal ARF
(A) Decreased perfusion without cellular injury
(B) Intact renal tubular and glomerular functions
(C)Reversible if underlying cause is corrected in time. ( Hypovolemia, Renal hypoperfusion, Hypotension)
• early stage: functional~~ late stage: organic ~~
(D) Characteristics of urine: oliguria, specific gravity ,
sodium , urinary sediment(-)
• (II) Intrarenal failure - Diseases of the renal parenchyma (肾实质) , specifically involving the renal tubules, glomeruli, interstitium
Vascular diseases Interstitial diseases Acute glomerulonephritis Diseases in tubules
Acute tubular necrosis (ATN)
Cause and classification
Diseases in tubules:Acute tubular necrosis (ATN)(80%)■Long time of renal ischaemiashock, dehydration, hemorrhage denaturalization ■Renal poisoning:Extrinsic : chemical agents (carbon tetrachloride 四氯化碳 ) heavy metals (mercury 水银 ) X-ray contrast medium biological toxin : some mushroom, snake venoms
drugs : sulfonamides 磺胺药物 , kanamycin 卡那霉素
Intrinsic:hemoglobin, myoglobin , uric acid
Difference between pre-renal and intrarenal ARF
Pre-renal Intra-renal
Urine specific gravity > 1.020 < 1.015
Urine osmotic pressure (mmol/L) > 500 < 350
Urine sodium(mmol/L) < 20 > 40
Ucr/Scr > 40:1 < 20:1
Urinary sediment (±) (+)
Urine protein (-) +~++++ Mannitol test urine volume urine volume(-)
• (III) Postrenal failure - Diseases causing urinary obstruction from the level of the renal tubules to the urethra
Tubular obstruction from crystals Ureteral (输尿管) obstructio
n
Cause and classification
renal pelvis
ureter
urinary bladder
Characters of Post-renal ARF
1) intact renal tubular and glomerular functions
2) reversible if underlying cause is corrected in
time (To rule out the obstruction quickly is very important.)
III Pathogenesis of ARF
Most of the manifestations of ARF are caused by the decreased urine volume.
Waste substance↑
The basic pathogenesis of ARF is to explain the reasons of decreased urine volume.
• GFR and tubular reabsorption are the main factors to determine the urine volume.•Glomerular-tubular balance
1% excrete• Decreased GFR and increased reabsorption in tubule will lead to decreased urine volume.
efferent
arteriol
GFR
Pathogenesis of ARF (induced by ATN)
(I) Changes of renal hemodynamics (effe
cts on glomerular function)
(II) Effects of tubular injury
(III) Glomerular Kf↓
(I) Changes of renal hemodynamics
1 Decreased renal blood flow
Inferior vena cava
Adrenal gland
Kidney
Aorta
Ureter
Bladder
Urethra
Renal blood flow: 20% ~ 30% of cardiac output(1200 ml/min).
Net Filtration Pressure
Blood hydrostatic pressure(BHP) 60 mmHg outColloid osmotic pressure(COP) -32 mmHg inCapsular pressure(CP) -18 mmHg in
Net filtration pressure(NFP) 10 mmHg out
NFP
BHP 60 out
COP 32 in
CP
10 out
18 in
•Systemic BP<80mmHgRenal artery BP is decreased
Glomerular hydrostatic pressure is decreased
Obstruction of urinary tract
Increased Bowman’s capsule pressure
Glomerular effective filtration pressure is decreased Decreased urine volume
(A)Decreased systemic pressure (B)Increased tubular pressure
Glomerular colloid osmotic pressure
Glomerular hydrostatic pressure
Bowman’s capsule pressure
Afferent arterioleefferent arteriole
1)Decreased renal blood presure
BP < 80mmHg
CO RBF
BP (50-70mmHg) GFR (1/2 – 2/3)
BP(40mmHg) GFR = 0
2) Renal vasoconstriction
Shock and trauma (low CO)
Increased activity in sympathetic system
Constriction of afferent arteriole
RBF decrease
Decreased urine volume
Baroreceptor in aortic arch and carotid sinus
Contraction of renal artery
(A)Increased activity of sympathetic system
Low renal artery
pressure
Increased Na+ in the distal tubule stimulate the Macula densa
Stimulate the release of renin from the
juxtaglomerular apparatus
Constriction of afferent artery(AII)
Decreased GFR
(B)Increased activity of renin-angiotension system
Ischemia and poisoning
Injury of proximal tubule and reduced Na+ reabsorption
Constriction of afferent arteriole
Injury of endothelium of renal vessels by hypoxia, acidosis
Increased synthesis and release of endothelin
Decreased effective filtration
pressure and GFR
Decreased urine volume
(C) unbalance of endothelin and NO
decreased synthesis and release of NO
• Kidney is the main organ to produce PGE2.
• The role of PGE2 is dilating blood vessels.
• The production of PGE2 is reduced before the development of ARI caused by gentamycin( 庆大霉素 )poisoning.
(D) Decreased production of vasodilatory prostaglandins (PGE2)
3 ) Renal vessel obstruction
A swelling of endothelial cell
ischemia Na+ - K+ - ATPase
Renal toxic substances
cell membrane permeability
calcium pump dysfunction
free radical endothelial cellular injury
B microthrombus formation in renal vessel
Calcium overload
Cell edema
(I) Changes of renal hemodynamics
2. Renal blood flow re-distributionrenal cortex ischemia GFR
renal medulla hyperemia Renal tubular injury
(II) Renal tubular injury
1 Morphologic changes
①morphologic change
•
Muddy Brown Cast
White blood Cell Casts
Red blood Cell Cast
② character of renaltubule cell damage A.Necrotic lesion
tubulorrhexis lesion( renal poisoning and renal ischemia persistently )
: involve all renal tubule , especially loop of Henle.
focal necrosis of nephron,
epithelial cell necrosis
basement membrane is destroyed
nephrotoxic lesion (Renal poisoning) :
involve proximal tubule , all Nephron damage , epithelial cells necrosis,
basement membrane is integrity
B.Apoptotic lesion : distal tubule
NaNa++ 、、 KK++-ATP-ATP 酶↓酶↓ Ca2+-ATP 酶↓
细胞内钠水潴留 胞浆内游离钙↑
细胞内 Ca2+ 超载
ATP ↓ATP ↓
缺血、中毒缺血、中毒
细胞水肿
OFROFR 生成生成↑ ↑
清除↓ 清除↓
脂质过氧化
GSH ↓GSH ↓
磷脂酶活性↑磷脂酶活性↑
PGs 、 LTs
细胞损伤 细胞损伤 (( 坏死;凋亡坏死;凋亡 ))
线粒体 Ca2+↑
ADPADP 、毒、毒物物
细胞损伤机制(了解)
1 ) Tubule obstruction
2)Loss of tubule integrity: initial urine back-leakage
2 Effect of tubular injury
1 ) Tubule obstruction
Reduced urine volume
Injury of proximal tubule cells ( necrosis)
Long time of renal ischemia
Renal poisoning
Detach from basement membrane and slough into the tubule lumen and become impacted (tube cast)
Increase Bowman’s capsule pressureTubule obstruction
Urine flow
Denudedtubularmembrane
Injuredtubularcells
Obstructionfrom debris andnecrotic cells
②Loss of tubule integrity ( passive back-leakage )
Severe ischemia and poisoning of tubule
Epithelial cell necrosis and loss of tubule integrity (become leaky)
Back leaking of urine to peritubular interstitial space
Press the tubule
Decreased urine volume
Press blood vessels
↑ intratubular pressure
↓ RBF
high interstitial pressure
43
Glomerular lesion
filtration surface area
Glomerular permselectivity
GFR
(III) Glomerular Kf↓
IV Clinical Course and manifestation
Two types of ARF:
oliguric (<400ml/d) ARF
nonoliguric (>400ml/d) ARF.
Clinical Course and manifestation
1 Oliguric phase ( days ~ weeks ) Manifestations:
a) changes of urine
b) azotemia
c) metabolic acidosis
d) hyperkalemia
e) Water intoxication
( I ) oliguric ARF
A changes of urine
(a) reduced urine volume: less than 400 ml /24h (oliguria) less than 100 ml/24h (anuria)Mechanism:RBF decrease, renal tubule obstruc
tion and urine back-leakage
(b) urine sediment investigation: In prerenal ARF: (- or +?) In ATN: (+) contain : RBC, WBC, epithelial cells
and casts
(c) specific gravity and osmolality:
ATN: Low specific gravity =1.010~1.015 (N:1.015-1.025)
Osmolality of urine = or < plasma
Cause: The ability of concentration and dilution is lost in ATN. Pre-renal AFR:
(d) urinary Na+ concentration:
In pre-renal ARF with normal reabsorption of tubule, urine [Na+] <20 mmol/L
In ATN, urine [Na+] >40 mmol/L
Actually, during oliguria, the amount of sodium entering Bowman’s capsule is decreased, the [Na+] in urine is elevated because of deficient tubular reabsorption of sodium.
B Water intoxication (Hypotonic hypervolemia, dilutional
hyponatremia ) Causes: (a) oliguria with more water intake (b) increased production of metabolic water (catabolism) (c) Transfuse fluid↑
Fluid retention
Hypervolemic hyponatremia
Cell edema
C Azotemia (NPN>40 mg/dl)
(a) Concept of azotemia: increased concentration of nonprotein nitrogens (NPN) i
n the blood. (normal: 20~35 mg/dl)
The nonproteins include urea, uric acid, creatinine etc.
(b) Reasons : a) oliguria b) increased catabolism of proteins.
血浆尿素氮 (blood urea nitrogen , BUN)
常用指标
内生肌酐清除率 (creatinine clearance rate, CCr )
血浆肌酐 (serum creatinine, SCr)
D Hyperkalemia most serious
• Urinary excretion of K+
• Tissue destruction
• Metabolic acidosis
• Transfuse non-fresh blood, high K+ diet
Hyperkalemia
Movement of K+ from cells into ECF
E Metabolic acidosis progressive, difficult to correct
• GFR excretion of acid production
• Secretion of H 、 NH3 , reabsorption of HC
O3–
• Catabolism , acid production
Metabolic acidosis
Hyperkalemia
2 Diuresis phase ( 4W )
Diuresis phase begins if the urine volume is over 400 ml/L, which reflects the improvement of ARF.
(A) Causes of diuresis: a) Normal RBF and no tubule obstruction. b) Concentration function of tubule is not recovered completely. Water and sodium can not be absorbed normally. The osmolality of urine remains low. c) Osmotic diuresis.
(B) manifestations of diuresis phase:
• polyuria , >400 ml/d ;• Early stage : Hyperkalemia, Azotemia , Metabolic acidosi
s
• Late stage : dehydration, hypokalemia, hyponatremia, infe
ction. 25% of the deaths in ARF occurs in diuresis phase.
3 Phase of functional recovery
The process of full recovery can take up to a year or more.
50% cases are restored to health.
50% cases become to CRF or die.
Influence factors: (a) presence or absence of preexisting renal disease
(b) age of patients
(c) length of the oliguria phase
(II) Nonoliguric ARF
Some patients may develop an acute loss of renal function without oliguria (urine volume>400 ml/day).
Characters:• higher GFR than oliguria ARF, • character of urine: volume 1280ml/24h,lower osmolality ,low specific gravi
ty ,higher urinary Na+ concentration than normal(lower than oliguric ARF)
• fewer complications,• low mortality rate• no or mild hyperkalemia • still high BUN Nonoliguric oliguric
V Treatment principles
(I) Prevention
1) Identify at risk patients, treat the underlying disease ;
Avoid nephrotoxic agents
2) Monitor serum electrolytes
Treatment principles
(II)Treatment • Make the patient safe
– Volume overload– Hyperkalemia– Control Azotemia– Acidosis– infection
• Specific treatments dialysis
Fluid therapy
• Fluid therapy needs to be closely monitored to maintain normovolemia.
• Fluid intake= insensible fluid loss
+urine volume
+ any ongoing losses
- metabolic water
For hyperkalemia
Oliguric renal failure is often complicated by hyperkalemia, increasing the risk in cardiac arrhythmias
Treatment of hyperkalemia: • sodium bicarbonate• insulin + hypertonic glucose• dialysis
nutrition
• provide adequate caloric intake
• limit protein intake to control increases in BUN
• minimize potassium and phosphorus intake
• limit fluid intake
For metabolic acidosis• NaHCO3 may be administered
§3 Chronic Renal Failure, CRF
• Definition
• Etiology
• Pathogenesis
• Alteration of Metabolism and Function
• Prevention & Treatment
I Definition
Dysfunction of excretion and endocrine
etiological factors destruct nephron
waste product , acid-base and electrolyte disorders , dysfunction of endocrine
65
II Causes of CRF
• Renal diseases : chronic glomerulonephritis(NO.1) et al
• Vascular disorders : diabetes mellitus 、 hypertensive disease 、 Periarteritis nodosa( 结节性动脉周围炎) , et al
• renal interstitium:chronic pyelonephritis( 慢性肾盂肾炎) , Chronic nephritis et al
• Urinary tract obstruction : urinary calculus( 尿结石) ,tumor,prostatic hyperplasia (前列腺增生) et al
66
• compensatory stage
• Renal insufficiency stage
• Renal failure stage
• Uremia stage
III Clinical Course of CRF
67
stage
Ccr
( ml/min )
BUN
(mmol/L)
Cr
(umol/L)
Clinical symptoms
compensatory >50 <9 <178 Primary disease,no specifical symptoms
Renal insufficiency
20 ~50
9 ~ 20 186 ~ 442
fatigue , mild anemia , digestive tract discomfort
Renal failure 10 ~20
20 ~ 28 451 ~ 707
anemia , metabolic acidois , hypocalcemia 、 hyperphosphorus 、polyuria and nocturia
Uremia <10 >28.6 >707 Uremic symptoms
68
• Intact nephron hypothesis
• Glomerular hyperfiltration hypothesis
• Renal tubular-renal interstitium hypothesis
• Trade-off hypothesis
IV Pathogenesis of CRF
69
• Intact nephron hypothesis
causes
Progressive reduction in the number of nephrons
Destroy nephron persistently
Renal compensation insufficiency
Renal failure
Compensatory glomerular hyperfiltration
Glomerulosclerosis
70
Renal tubular-renal interstitium hypothesis
Causes(Urine protein, cytokine,inflammatory factor, complement)
renal tubular epithelial cell
apoptosis,necrosis
Renal tubular atrophy
Renal tubular epithelial cell activated and proliferati
on
Renal function aggravate progressively
Trade-off hypothesis•
Decreased GFR
Increased concentration of some solutes
Stimulate release of related regulatory factors (hormones)
Increase the solutes excretion
(good)Further metabolic disorders
Aggravate the CRF (bad)
Decreased GFR
Increased serum concentration of phosphate
Stimulate release of parathormone (PTH) by parathyroid glands
Increase the phosphate excretion from kidneys (good)
Stimulate calcium release from bone
[P] ,[Ca2+] osteomalacia (bad)
Decreased phosphate excretion
Decreased serum ionized calcium
73
V Changes of Function and Metabolism
(I) characteristics of urine :1.volume : nocturia
polyuria ( >2000ml/d ) oliguria oliguria(<400ml/d)
2.specific gravity : hypotonic urine (early stage) 、 isotonic urine(late stage)
3.sediment : Proteinuria( 蛋白尿)、 hematuria (血尿)、 pyuria (脓尿)、 casts
initial urine flow rateosmotic diuresis
Renal concentrating function
74
尿渗透压的变化
1.035
1.020
1.012
1.008
1.002
低渗尿
正常
等渗尿
尿
相对
密度
75
• BUN is not parallel to renal function
• Plasma creatinine
endogenous creatinine clearance rate
---- 反应肾功能
II azotemia (NPN>28.6mmol/L)
CCR=Ucr × Vu
Pcr
III acid-base and electrolyte disorders
1Dehydration (A) due to polyuria, nocturia.
The ability to dilute the urine is preserved with a reduced ability to concentrate the urine. (B) Diarrhea, vomiting may quickly cause dehydration. Dehydration will lead to hypovolemia, decreased GFR and further deterioration of renal function.
The water intake should be of sufficient quantity and frequency (day a
nd night) to compensate for the polyuria.
2 Hypervolemia, General edema
Congestive heart failure.
Cause:
excess water intake
fixed urine volume(oliguria)
3. Sodium imbalance
In normal persons sodium excretion may vary from nearly zero to more than 20g/day in response to a variable intake.
Patients with CRF lose the ability to regulate the sodium balance.
(A) Sodium deficiency and hyponatremia
Increased loss from kidneys : Osmotic diuresis,renal tubule fluid flow quicky (intact nephron ),
methylguanidine inhibit sodium reabsorption
Vomitting , diarrhoea
(B) Sodium excess (which leads to edema, hypertension)
Oliguria in terminal stage
Taking more
4.Potassium imbalance
(1) Normal serum [K+] : maintained until the stage of renal failure. (GFR=10%~25% )
Causes of normal serum [K+]
(A) increased excretion from renal tubular and collecting duct(aldosterone secretion increase)
(B) increased excretion from intestine.
(2) Hypokalemia
Causes:A) polyuria in early stage
B) vomiting
C) diarrhea
D) restrict intake
(3) Hyperkalemia
Causes:A) oliguria in end-stage
B) acidosis
C)acute infection
82
5. Ca P :
P(>1.6mmol/L) :early stage : compensation ( PTH ) late stage: nephron bone dissolve
Ca(<2.25mmol/L)
P 【 Ca 】 × 【 P 】 =40
calcium phosphate
calcitonin
1,25-(OH)2VitD3 Absorption of intestine Ca
Toxic substance damage intestinal tract
Intake
6. Acidosis
1) impaired ability of H+ excretion, reduced HCO3- reabsorption.
2) impaired ability of NH4 + excretion, reduced HCO3- regeneration.
3)Sodium excretion increase, secondary RAS activation(metabolic acidosis with normal AG)
4) impaired ability of fixed acids excretion ( phosphate, sulfate, organic acids) metabolic acidosis with AG increase
Effects of acidosis
Anorexia, nausea and lethargy (depression of mental activity) may be due in part to the acidosis.
Kussmaul respiration (deep sighing respiration) is for increasing CO2 excretion.
•
83
84
(IV) Renal hypertension
(1) Fluid and sodium retention(Na+-dependent,75%)
(2) Renin (renin-dependent)
(3) kinin 、 PGE2
85
(v) Hemorrhagic tendency
• Toxic substance inhibite the function of platelet
• PF3
Bleeding
Platelet counts are normal.
Platelet function is impaired by uremic toxins.
adhesion
aggregation
(VI) Anemia and bleeding(97%)
Concept: normochromic, normocytic anemia, too few red blood cells
1)Primary factors of renal anemia:
(A) Deficient production of RBC
EPO (erythropoietin) is a red blood cell growth factor produced by kidney (90%), which can stimulate the production of RBC in bone marrow.
EPO is produced by the kidneys
blood
stimulates the production of RBC in bone marrow
damaged kidneys
_
Uremic toxins may inactivate EPO.
_
Uremic toxins may suppress the response of bone marrow to EPO.
_
(B)Reduced red blood cell survival
The RBC lifespan is shortened by uremic toxins.
Secondary factors of renal anemia:
Iron deficiency
Drug effects
bleeding
Symptoms of anemia
• Fatigue• Loss of appetite
91
(2)1,25- ( OH)2Vit D3 : absorption of intestine Ca
(1)P Ca and secondary hyperparathyroidism : high turnover bone disease
(3) acidosis : bone mineral lysis , decalcificationA)Bone salt leaves the bone to blood for buffering increased [H+]B)Acidosis decreases the formation of active vit.D3.C) Acidosis decreases the calcium absorption from the gut.
(VII) renal osteodystrophy
(4) aluminum poisoning : low turnover bone disease
Principles of treatment
• 1 Focus on primary disease treatment• 2 alimentary control • Nutritional management • Protein restriction• Salt-restriction diet• 3 treat complications• 4 dialysis• 5 transplantation
92
93
End-stage renal failure
uremiaARFCRF
Toxin Intoxicationsymptom
94
source : 1. Metabolite
2. Ectogenesis toxin
3. Ectogenesis toxin metabolite
4. Normal activity material
Uremia toxin
95
common : urea, uric acid,guanidine ( methylguanidine 、creatinine ) , amines and phenol , middle molec
ules 、 PTH
Uremia toxin
96
change of function and metabolism
97
肌肉骨骼系统肾性骨病生长迟缓
心血管系统高血压
心力衰竭心包炎
代谢葡萄糖耐量降低,负氮平衡,高脂血症,代酸
内分泌系统甲低,甲旁亢,垂体 -性腺功能失
调
皮肤瘙痒、干燥、脱屑和颜色改变,尿素霜
呼吸系统库氏呼吸,氨臭,纤维性胸膜炎,肺水肿
消化系统食欲不振、厌食、恶心、呕吐或腹泻,溃疡性炎症
神经系统头痛、头昏、烦燥不安、抑郁、嗜睡甚至昏迷,
周围神经病变
血液和免疫贫血
出血倾向易感染尿毒症尿毒症
98
Treatment principle
1 、 treatment of the primary disease 2 、 dialysis therapy 3 、 renal transplantation