Chapter 13 Renal Failure

§1 Concept & Introduction• Kidney structure: Nephron (Glomerulus & Tubules) ,/ Renal interstitium

,/ Kidney blood vessels, / Urinary tract outside kidney( Ureters & bladder )

• Many pysiologecal function:⑴Excretory function Regulatory function ⑵ ⑶Endocrine and metabolic function

Excretory function & Endocrine function

• Excretory functionFiltration function in glomerulus

Reabsorption and secretion

In tubules

GFR (125ml/min) 99%

Urine (1.5~2L / d )

Removal of waste products,drug and toxic substances

Maintenance of water, electrolyte and acid-base balance

Maintenance of volume and composition in urine

Azotemia,Hyperkalemia,Metabolic acidosis,Water intoxication,Oliguria,Anuria/Non-oliguria, Alteration of composition in urine

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Endocrine functions:• Renin (R) ↑ Renal hypertension• Prostaglandins(PG) ↓ Renal hypertension • Kallikrein & Kinin ↓ Renal hypertension• Erythropoietin(EOP) ↓Renal anemia • 1,25-(OH)2-D3 ↓Renal osteodystrophy hyperphosphatemia hypocalcemia• Intrarenal R-A system• Intrarenal K-K-P system • Intrarenal ET-NO/NOS system

Acute renal failure, Chronic renal failure, Uremia

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§2 Acute Renal Failure (ARF)1. Concept ARF is a complex pathophysiologic process and is an i

mportant clinical syndrome. It is characterized by sudden decline in renal excretory function over a period and usually associated with oliguria, anuria / non-oliguria, Alteration of composition in urine, azotemia, hyperkalemia, metabolic acidosis and water

intoxication.

2. Causes (1) Prerenal causes(renal hypoperfusion) Prerenal ARF Blood supply to nephron↓----CO↓,/ Bp ↓,/ BV ↓,/ Constriction of kidney blood vessels.

Alterations of volume and composition in urine:

Prerenal

causesRenal perfusion ↓ GFR↓

ADH↑,ADS↑

Oliguria (<400ml/d) orAnuria (<100ml/d)Urinary Na+ ↓(<20mmol/L )Urine specific gravity ↑(>1.020)Urine osmolality ↑(>400mosm/L)Ucr / Pcr ↑(>40:1)RFI < 1FENa <1Urine sedimentary assay: (-)

RFI=Urinary Na+∕ Ucr/Pcr FENa=Urinary Na+/blood Na+/ Ucr/Pcr

(2) Intrarenal causes (intrinsic renal injury) Intrarenal ARF Injury of renal tissue itself (glomerulus,/ tubules,/ blood vessel

s)1) Diseases of glomerulus--- Acute poststreptococcal glomerulonephritis,/ Vasculitis 2) Acute tubular necrosis (ATN)---Severe renal ischemia ,/ Renal po

isoning (Heavy metals,/ ethylene glycol ,/ Insecticide ,/ Poisonous mushrooms, / Carbon tetrachloride ) A number of chemical agents can selectively and critically destroy rena

l tubular cells. 3)Renal vessel injury--- Embolism of renal artery,/ DIC 4)Renal interstitial injury---Acute interstitial nephritis,/ Bilatenal pyelo

nephritis

Alteration of volume and composition in urine:

Severe renal ischemia

Renal poisoinig Renal perfusion ↓ GFR ↓

ATN

Oliguria,Anuria or

Non-oliguria ( ≈1000ml/d)

Urinary Na+ ↑(>40mmol/L )

Urine specific gravity ↓(<1.015)

Urine osmollarit↓ (<350mOsm/L)

Ucr / Pcr ↓(<20:1)

RFI >1

FENa >2

Urine sedimentary assay: Proteinuria, Cylindruria,Blood urine.(3)Postrenal causesPostrenal ARF

Obstructive disorders in urinary tract--- large stone,/

Blood clots,/ Scarring of injury or surgery.

3.Pathogenesis of ARF1.Renal hemodynamic alterations (Vasomo

tor theory) → GFR↓(1)Decrease of renal perfusion pressure arterial blood pressure↓→ Renal blood pressure↓

(2)Renal vasoconstriction Renin-angiotensin system ↑AT ↑Ⅱ Sympathetic adrenergic system↑ Catecholamine↑, Prostacyclin↓,Endothelin(ET)↑,Nitric oxide(NO)↓, 3)Renal vascular endothelial swelling Hemodynamic factors play an important role predomina

tly during the initiation of the acute renal insult.

(4)Ischemia-reperfusion injury of Kidney. Calcium overload(Calcium paradox) / Active xan

thine oxydase (XO) Oxygen flee radicals obstruct renal capillary and cause tubular necrosis

2.Renal glomerular injury Acute glomerulonephritis,lupus nephritis→glomerular

membrane damage→ filtration area↓→GFR↓

3. Renal tubular injury(1)Passive backflow (Back-Leakage theory)

(2)Tubule obstruction (Tubule obstruction theory)

4.Renal cell injury(endothelial 、 mesangial cells etc.)

Renal ischemia,renal poisons

Injury of renal tubular cells

Loss of Tubule Integrity Cellular Debris Back-leakage of crude urine Tubular Obstruction

↓ Effective Filtration pressure

↓Glomerular filtration rate

Oliguria

4.Alterations of metabolism and function

• Oliguric Acute Renal Failure1.Oliguric phase(1) Urinous alterrations :Oliguria / Anuria, Alteration of composition

in urine. as following(2) Azotemia ---an abnormally high level of nitrogenous wastes (bloo

d urea nitrogen, uric acid, serum creatinine) Autotoxication Syndrome(3) Water intoxication

Diluted hyponatremiaCerebral edema, Pulmonary edema, Cardiac insufficiency

(4) Hyperkalemia Myocardial poisoning(5) Metabolic acidosis Hyperkalemia, Disfunction of CNS

2.Diuretic phase

Urine volume>400ml/d, → >3000ml/d.

In the early pase, BUN, serum creatinine, potassium, and phosphate may remain elevated or continue to rise even though urine output is increased. In the late phase, dehydration,hypokalemia,hypernatremia are easy to occur.

3. Recovery phase

Nonoliguric ARF is another type of ARF,in which renal pathological changes And clinical presentations are relatively slight, so the disease is shorter, and Prognosis is better. Its main characters include urine output not ①decrease (400 ～ 1000ml/d); special gravity②of urine is low and fixed, and urinous sodiumContent is low; existence of azotemia. ③The mechanism for this type of ARF is Notunderstood currently.

§3 Chronic Renal Failure(CRF)

1. Concept CRF a complex pathophysiologic process and is an important clinical syndrome It is characterized by progressiveand irreversible destruction of renal tissue.The Consequences of renal destruction express in progressive deterioration of the filtration,reabsorptive functions and endocrine functions of the kidney, damage usually proceeds slowly, terminating in death when a sufficient number of nephrons have been destroyed.

The end stage of CRF is uremia.

2. Causes

Any disorder that permanently destroys nephrons may result in CRF ( by glomeruli, tubules, renal interstitium, blood vessels ,lower urinary tract,)

Exemplum :1) Chronic glomerulonephritis---by destruction of glomeruli.

2) Chronic pyelonephritis---by fibrosis of renal pelvis and medulla.

3) Hypertension nephropathy---by narrowing of renal arteries.

4) Renal calculi, urethral or ureteral stricture---by damage to

the nephrons caused by fluid back-pressure secondary to obstruction.

3.Clinical Course of CRF(1) Stage of decreased renal reserve(Silent stage) Ccr>30%, BUN and serum creatinine(Cr) = nomal, Renal reserve ↓.

[ Clearance creatinine=Ucr x V / Pcr ≈ GFR ]

(2)Stage of renal insufficiency Ccr=25~30%, BUN and Cr ↑, Polyuria, Nocturia,

Mild anemia and acidosis.

(3)Stage of renal failure Ccr=20~25%,Marked anemia, severe acidosis, hypocalcemia,

hyperphosphatemia, BUN and Cr↑↑.(4)Stage of uremia

Ccr<20%,A series of uremic symptoms, The uremic syndrome

affects every system in the body.

.

4.Pathogenesis of CRF(1) Intact nephron hypothesoisIntact nephron hypertrophy (filtration↑reabsorption↑)Destroyed nephron (filtration↓reabsorption↓)

(2) Trade-off hypothesis “Trade off” refers a process that organism develops a new lesion by Correcting an old damage:

AS the nephrons are progressively destroyed, increased blood concentration of some solutes stimulates secretion of some related regulatory factors (such as hormones) in order to maintain the excretion function. At the same time, however, high blood levels of the regulatory factors will result in further metabolic disorder. It is termed ”trade-off”.

GFR↓→filtration of phosphate↓→plasma phosphate↑and

plasma calcium↓→PTH↑→plasma phosphate(N)…

GFR↓↓→Plasma phosphate↑↑→PTH↑↑→breakdown of bone

→hyperphosphatemia and renal osteodystrophy

(3)Glomerular hyperfiltration hypothesis In the single nephron compensatory intraglomerular

hyperfusion and hyperfiltration, together with intraglomerular hypertension result in progressive glomerular sclerosis and eventual glomerular death

Several hormones, growth factor, biologically active lipids cytokines (AT ,TGF-Ⅱ β,IL-1, TNF ) influence mesangial and interstitial cell proliferation and

extracellular matrix deposition

→ nephrons↓→ vicious circle → CRF

(4)Lesion of tubular and interstitial cells

5.Alterations of metabolism add function

(1)Disturbance of water, electrolyte and acid-base

①Disorders of water balance Nocturia (the urine volume in night time is about 2~3

times in day time, or more than 750ml )

at GFR<40ml/min

Polyuria (>2000ml/d) at GFR<30ml/min

Oliguria (<400ml/d) at GFR=5~10ml/min

Hyposthenuria(<1.020), Isostheuria(1.010, 285mOsm/L)

Proteinuria ,Cylindruria

.

.

②Disorders of electrolyte metabolism

• Disorders of sodium metabolism

Hyponatremia ( when polyuria)

↓

hypernatremia (When oliguria)

• Disorders of potassium metablism

Serum potassium concentration is usually maintained normal range until GFR<25%.

Polyuria in early CRF→hypokalemia.

Oliguria in end-stage CRF→hyperkalimia.

• Disordrs of calcium-phosphate balance Hyperphosphatemia GFR↓→filtration of phosphate↓→plasma phosphate↑and plasma calcium↓→PTH↑→plasma phosphate(N)… GFR↓↓→Plasma phosphate↑↑→PTH↑↑→breakdown of bone→hyperphosphatemia.

Hypocalcemia hyperphosphatemia / vitaminD3 metabolism dysfunction/

PTH↑calcitonin secretion ↑ / some toxic substances damage GI to reduce Ca2+absorption.

• Metabolic acidosis Impaired ability of the kidney to excrete, H+/ NH4

+ excretion is decreased GFR↓→retention of phosphate,sulfate and other organic anions

(2) Azotemia

Non-protein nitrogens( NPN)>28.6mmol/L or >40mg/dl

Blood urea nitrogen( BUN)>3.75~7.14mmol/L or >10~20mg/dl

Plasma creatinine (Scr)>0.9~1.8mg/dl

[ Creance clearance=Ucr x V(ml/min) / Pcr ≈GFR .]

Blood uric acid >3~5mg/dl

(3)Renal hypertension

Sodium-dependent hypertension

Renin-dependent hypertension

PGE2↓,PGI2↓and KK-K↓→hypotension

(4)Renal osteodystrophy which includes renal rickets (for children),adult

osteomalacia, osteitis fibrosa,osteoporosis

Chronic renal Failure

GFR↓

1,25(OH)2Vit.D3↓ Elimination of phosphate ↓ Acidosis

Plasma phosphate↑

Deposition of Gastrointestinal

Calcium in bone↓ absorption of calcium↓

Hypocalcemia

Secondary hyperparathyroidism

Renal osteodystrophy

(5) Renal anemia MechanismReducing erythropoiten / Cumulating of toxic substances in body / Bleeding / Toxic substances destroy RBCs / Reducing absorption or utilization of iron and protein

(6)Tendency to hemorrhageMechanism: by inhibiting role of the cumulating renal poisons (such as urea, Carbamidine,etc.) on function of platelet

§4 Uremia1.Concept of uremia Uremia is the most severe stage of acute or chronic Renal

failure .Besides disorders of water and electrolyte metabolismand acid-base imbalance, and renal endocrine function, thepatients with uremia will manifest a series of autotoxication syndroms caused by accumulation of endogenous poisons.

2.Clinical manifestation of uremia(1)Nenrological signs(2)Cardiovascular signs(3)Respiratory signs(4)Gastrointestinal signs (5)Endocrine signs(6)Signs of skin (7)Immunity signs(8)Disorders of metabolism

3.Pathogenesis of uremia

(1) Uremic Toxins

①Urea

②Guanidine compound

③Amines and phenols

④Middle molecules(mol.wt.500~5000D)

(2) Parathyroid hormone (PTH)

(3)Aluminum

Pathophysiological basis of prevention and treatmentFor the treated of ARF are as following:1.To maintain fluid and electrolyte, acid-base, and solute homeostasis, such as treating hyperkalemia and correcting metabolic acidosis2.To control the level of blood nonprotein nitrogen.3.To prevent subsequent infection.4.To promote healing and renal recovery.5.To permit other support measures, such as nutrition to proceed without limitation.6.Renal replacement therapy may be provided by peritoneal dialysis or intermittent hemodialysis.For the treated of CRF and uremia are as following1.To treat the primary renal disease.2.To treat reversible aggravating factor.3.To prevent or slow the progression of real disease.4.To prevent and treat end stage renal failure.5.Other treatment.