department of pathophysiology, shandong university school of medicine 薛冰 renal insufficiency

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

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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

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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

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• compensatory stage

• Renal insufficiency stage

• Renal failure stage

• Uremia stage

III Clinical Course of CRF

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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

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• Intact nephron hypothesis

• Glomerular hyperfiltration hypothesis

• Renal tubular-renal interstitium hypothesis

• Trade-off hypothesis

IV Pathogenesis of CRF

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• Intact nephron hypothesis

causes

Progressive reduction in the number of nephrons

Destroy nephron persistently

Renal compensation insufficiency

Renal failure

Compensatory glomerular hyperfiltration

Glomerulosclerosis

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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

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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

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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

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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

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(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