Acute Renal Failure

Matthew L. Paden, MD Pediatric Critical Care Emory University Childrens Healthcare of Atlanta at Egleston

Structure and Function of the Kidney

  

Primary unit of the kidney is the nephron 1 million nephrons per kidney Composed of a glomerulus and a tubule Kidneys receive 20% of cardiac output
Renal Lecture Required Picture #1

Renal blood flow

Aorta Renal artery interlobar arteries interlobular arteries afferent arterioles glomerulus efferent arterioles  In the cortex peritubular capillaries  In the juxtamedullary region vasa recta  Back to the heart through the interlobular intralobar renal veins


Glomerular Filtration Rate

 

Determined by the hydrostatic and oncotic pressure within the nephron Hydrostatic pressure in the glomerulus is higher than in the tubule, so you get a net outflow of filtrate into the tubule Oncotic pressure in the glomerulus is the result of non-filterable proteins non

Greater oncotic pressure as you progress through the glomerulus

GFR = Kf (hydrostatic oncotic pressure)

Renal Lecture Required Picture #2

Glomerular Filtration Rate

 The

capillary endothelium is surrounded by a basement membrane and podocytes  Foot processes of the podocytes form filtration slits that :
 

Allow for ultrafiltrate passage Limit filtration of large negatively charged particles
Less than 5,000 daltons = freely filtered Large particles (albumin 69,000 daltons) not filtered

Tubular Function
 Proximal
   

Most of reabsorption occurs here Fluid is isotonic with plasma 6666-70% of sodium presented is reabsorbed Glucose and amino acids are completely reabsorbed

Tubule Function
 Loop


of Henle

Urine concentration and dilution via changes in oncotic pressure in the vasa recta Descending tubule permeable to water, impermeable to sodium Ascending tubule actively reabsorbs sodium, impermeable to water

Tubular Function
 Medullary

thick ascending limb critical for urinary dilution and most often damaged in ARF
 

ADH stimulates Na re-absorption in this area reMost sensitive to ischemia

Low oxygen tension, high oxygen consumption

Lasix use here inhibits the Na-K-2Cl ATPase Nawhich in the face of ARF, may decrease oxygen consumption and ameliorate the severity of the ARF

Tubular Function
 All


of those studies done in an in vitro model

In vivo, if you drop oxygen concentration even subsub-atmospheric you do not get tubular damage even with increased tubular workload In vivo models exist where you do see that damage, but appears to need a second hit

Tubule Function
 Distal
  

Tubule

ReRe-absorption of another ~12% of NaCl Proximal segment impermeable to water Distal segment is the cortical collecting duct and secretes K and HCO3

Tubular Function
 Collecting


Duct

 

Aldosterone acts here to increase Na reuptake and K wasting ADH enhances water re-absorption reUrea re-absorption to maintain the medullary reinterstitial concentration gradient

Acute Renal Failure - Definitions

 Renal

failure is defined as the cessation of kidney function with or without changes in urine volume  Anuria UOP < 0.5 cc/kg/hour  Oliguria UOP more than 1 cc/kg/hour


Less than?

Acute Renal Failure - Definitions

 70%

NonNon-oliguric , 30% Oliguric  Non-oliguric associated with better Nonprognosis and outcome  Overall, the critical issue is maintenance of adequate urine output and prevention of further renal injury.


Are we converting non-oliguric to oliguric with nonour hemofilters?

Acute Renal Failure - Diagnosis

 Pre-renal Pre Decrease in RBF constriction of afferent arteriole which serves to increase systemic blood pressure by reducing the shunt through the kidney, but does so at a cost of decreased RBF At the same time, efferent arteriole constricts to attempt to maintain GFR As GFR decreases, amount of filtrate decreases. Urea is reabsorbed in the distal tubule, leading to increased tubular urea concentration and thus greater re-absorption of urea into the blood. re

Creatinine cannot be reabsorbed, thus leading to a BUN/Cr ratio of > 20

PrePre-Renal vs. Renal Failure

Prerenal
BUN/Cr FENa Renal Failure Index UNa Specific Gravity Uosm Uosm/Posm >20 <1% <1% <20 mEq/L >1.020 >1.3

Renal
<20 >2% >1% >40 mEq/L <1.010 <1.3

>500 mOsm/L <350 mOsm/L

Renal Lecture Required Picture #3

Acute Renal Failure - Diagnosis

 Diagnosis


Ultrasound
Structural anomalies polycystic, obstruction, etc. ATN
 

poor corticomedullary differentiation Increased Doppler resistive index (Systolic Peak Diastolic peak) / systolic peak

Nuclear medicine scans

DMSA Static - anatomy and scarring DTPA/MAG3 Dynamic renal function, urinary excretion, and upper tract outflow

Acute Renal Failure

 Overall,


renal vasoconstriction is the major cause of the problems in ARF

Suggested ARF be replaced with vasomotor nephropathy

 Insult

to tubular epithelium causes release of vasoactive agents which cause the constriction


Angiotensin II, endothelin, NO, adenosine, prostaglandins, etc.

Regulation of Renal Blood Flow

 In

adults auto-regulated over a range of autoMAPs 80-160 80 Developmental changes

  

Doubling of RBF in first 2 weeks of life Triples by 1 year Approaches adult levels by preschool

 Renal


blood flow regulation is complex

No one system accounts for everything..

ReninRenin-Angiotensin Axis
 

For the one millionth time. Hypovolemia leads to decreased afferent arteriolar pressure which leads to decreased NaCl re-absorption which leads to decreased Cl representation to the macula densa which increases the amount of renin secreted from the JGA which increases conversion angiotensinogen to AGI to AGII which increases Aldosterone secretion from the adrenal cortex and ADH which leads to increased sodium and thus water re-absorption from the tubule which reincreases your blood pressurewhew

Renin Angiotensin Axis

Renal Lecture Required Picture #4

Renin Angiotensin Axis

 Renins


role in pathogenesis of ARF

Hyperplasia of JGA with increased renin granules seen in patients and experimental models of ARF Increased plasma renin activity in ARF patients Changing intra-renal renin content modifies intradegree of damage
Feed animals high salt diet (suppress renin production) renal injury less renal injury than those fed a low sodium diet

Renin Angiotensin Axis

 Not


the only thing going on though

You can also ameliorate renal injury by induction of solute diuresis with mannitol or loop diuretics (neither affect the RAS) No change in renal injury in animals given ACE inhibitors, competitive antagonist to angiotensin II

 Overall,

role of RAS in ARF is uncertain

Prostaglandins
 PGE


2 and PGI

Very important for renal vasodilation, especially in the injured kidney Act as a buffer against uncontrolled A2 mediated constriction
If you constrict the afferent arteriole, you will decrease GFR

 The

RAS and Prostaglandin pathways account for ~60% of RBF autoautoregulation

Adenosine
 Potent


renal vasoconstrictor

Peripheral vasodilator

 Infusion

of methylxanthines (adenosine receptor blockers) inhibits the decrease in GFR that is seen with tubular damage  Some animal models show that infusion of methylxanthines lessen renal injury in ARF

Adenosine
 But.


Likely not a major factor in ARF

Methylxanthines have lots of other actions besides adenosine blockade Adenosine is rapidly degraded after production IntraIntra-renal adenosine levels diminish very rapidly after reperfusion, but the vasocontriction remains for a longer period Finally, if you block ADA, creating higher tissue adenosine levels, and then create ischemia you actually get an enhancement of renal recovery

Endothelin


21 amino acid peptide that is one of the most potent vasoconstrictors in the body


Can be used as a pressor

 

Its role in unclear in normal state In ARF, overproduction by cells (both in and outside of the kidney) leads to decreased afferent flow and thus decreased RBF and GFR


Endothelin increases mesangial cell contraction which reduces glomerular ultrafiltration

 

Stimulates ANP release at low doses and can increase UOP AntiAnti-endothelin antibodies or endothelin receptor antagonists decrease ARF in experimental models

Nitric Oxide
 Produced

by multiple iso-enzymes of NOS iso In addition to its role in vasodilation, likely has a role in sodium re-absorption re

Give a NOS blocker and you get naturesis

 Important

in the overall homeostasis of

RBF  Exact mechanisms not worked out completelyat least when Rogers was written.

Obligatory Incomprehensible Pathway for Jim #1

Nitric Oxide
 Confusing


results

Ischemic rat kidney model inducing NOS causes increasing injury Hypoxic tubular cell culture model inducing NOS causes increasing injury But if you block NOS production, you get worsening of renal function and severe vasoconstriction

Nitric Oxide
 So

stimulation of NO in the renal vasculature will modulate vasoconstriction and lead to lesser injurybut  That same induction of NO in the tubular cells will cause increased cytotoxic effects

Dopamine
 Dopamine

receptors in the afferent

arteriole  Dilation of renal vasculature at low doses, constriction at higher doses  Also causes naturesis (? Reason for increased UOP after starting)  Renal dose dopamine controversy.

Renal Hemodynamics and ARF

 Conclusions.


Renal vasoconstriction is a well documented cause of ARF Renal vasodilation does not consistently reduce ARF once established Although renal hemodynamic factors play a large role in initiating ARF, they are not the dominant determinants of cell damage

ARF - Pathophysiology
 Damage

is caused mostly by renal perfusion problems and tubular dysfunction  Usual causes
  

HypoHypo-perfusion and ischemia Toxin mediated Inflammation

ARF Pathophysiology
 Hypo-perfusion Hypo  

Well perfused kidney 90% of blood to cortex Ischemia increased blood flow to medulla Outcome may be able to be influenced by restoration of energy/supply demands
Lasix example

Leads to tubular damage

ARF - Pathophysiology
 Oxidative
 

damage

Especially during reperfusion injuries Main players

Super-oxide anion, hydroxyl radical highly Superionizing Hydrogen peroxide, hypochlorous acid not as reactive, but because of that have a longer half life and can travel farther and cause injury distal to the site of production

ARF - Pathophysiology
 Ischemia


Damage to mitochondrial membrane and change of xanthine dehydrogenase (NAD carrier) to xanthine oxidase (produces O2 radicals) Profound utilization of ATP 5-10 minutes of ischemia you use ~90% of your ATP
Make lots of adenosine, inosine, hypoxanthine

ATP ADP AMP

Adenylosuccinate Hypoxanthine H20 O2 Xanthine H20 O2 Uric Acid H20 O2 CO2 Allantoin H2O2 H2O2

Adenosine Inosine

IMP

ARF - Pathophysiology


Once you get reperfusion, the hypoxanthine gets metabolized to xanthine and uric acid each creating one H2O2 and one super-oxide radical superintermediate Reactive oxygen species oxidize cellular proteins resulting in:
   

Change in function/inactivation/activation Loss of structural integrity Lipid peroxidation (leads to more radical formation) Direct DNA damage

ARF Pathophysiology
 Amount


of damage depends on ability to replete ATP stores

Continued low ATP leads to disruption of cell cytoskeleton, increased intracellular Ca, activation of phospholipases and subsequently the apoptotic pathways

Obligatory Incomprehensible Pathway for Jim #2

ARF Pathophysiology
 Amount


of damage depends on ability to replete ATP stores

Continued low ATP leads to disruption of cell cytoskeleton, increased intracellular Ca, activation of phospholipases and subsequently the apoptotic pathways

 This

endothelial cell injury sparks an immune response.that cant be good.

ARF - Prevention
 Maintenance


of blood flow

Cardiac output, isovolemia, etc

 Avoidance


of toxins

Aminoglycosides, amphoteracin, NSAIDs

 Easy

on paper.difficult in practice

ARF - Prevention
 Lasix


May have uses early in ARF May work by

Increasing flow through tubules, preventing obstruction Osmotic action, decreasing endothelial swelling Decreased blood viscosity with increased renal perfusion (???) Free radical scavenging

 Mannitol


ARF - Prevention
 Renal

dose dopamine.  Endothelin antibodies



No human trials More rapid improvement of renal function in animals Increased uptake of ADP to form ATP or cell membrane stabilization as a possible cause

 Thyroxine


ARF - Prevention


ANP


Improve renal function and decrease renal insufficiency ? Nesiritide role Adenosine antagonist prevents reduction in GFR. After ischemic insult, infusion of IGF-I, Epidermal GF, IGFHepatocyte GF improved GFR, diminished morphologic injury, diminished mortality

 

Theophyline


Growth Factors


None of these things are well tested..

ARF Prevention in Specific Cases

 Hemoglobinuria/Myoglobinuria


Mechanism of toxicity
Disassociation to ferrihemate, a tubular toxin, in acidic urine Tubular obstruction Inhibition of glomerular flow by PGE inhibition or increased renin activation

Treatments (?)
Aggressive hydration to increase UOP Alkalinization of urine Mannitol/Furosemide to increase UOP ?Early Hemofiltration

ARF Prevention in Specific Cases

 Uric
 

Acid Nephropathy

A thing of the past thanks to Rasburicase? Treatments

Aggressive hydration to drive UOP Alkalinization of the urine Xanthine oxidase inhibitors

ARF - Management
 Electrolyte


management

Sodium
Hyponatremia fluid restriction first, 3% NaCl if AMS or seizing

Potassium
Calcium/Bicarb/Glucose/Insulin/Kayexalate Hemodialysis

ARF - Management
 Nutrition
 

management

Initially very catabolic Goals:

Adequate calories Low protein Low K and Phos Decreased fluid intake

Renal Replacement Therapy

 Peritoneal

Dialysis  Acute Intermittent Hemodialysis  Continuous Hemofiltration

   

CAVH SCUF CVVH, CVVHD And others.

Peritoneal dialysis
Advantages
     

Disadvantages
       

Simple to set up & perform Easy to use in infants Hemodynamic stability No anti-coagulation antiBedside peritoneal access Treat severe hypothermia or hyperthermia

Unreliable ultrafiltration Slow fluid & solute removal Drainage failure & leakage Catheter obstruction Respiratory compromise Hyperglycemia Peritonitis Not good for hyperammonemia or intoxication with dialyzable poisons

Intermittent Hemodialysis
Advantages Disadvantages
     

Maximum solute clearance of 3 modalities  Best therapy for severe hyperkalemia  Limited anti-coagulation antitime  Bedside vascular access can be used


Hemodynamic instability Hypoxemia Rapid fluid and electrolyte shifts Complex equipment Specialized personnel Difficult in small infants

Continuous Hemofiltration
Advantages
       

Disadvantages

Easy to use in PICU Rapid electrolyte correction Excellent solute clearances Rapid acid/base correction Controllable fluid balance Tolerated by unstable pts. Early use of TPN Bedside vascular access routine

 

Systemic anticoagulation (except citrate) Frequent filter clotting Vascular access in infants

Indications for RRT



Still evolving.Generally accepted

          

Oliguria/Anuria Hyperammonemia Hyperkalemia Severe acidemia Severe azotemia Pulmonary Edema Uremic complications Severe electrolyte abnormalities Drug overdose with a filterable toxin Anasarca Rhabdomyolysis