application of the steady-state principle vivek bhalla, md division of nephrology stanford...

Application of the “Steady-state” Principle

Vivek Bhalla, MDDivision of Nephrology

Stanford University School of MedicineSeptember 1st 2015

Learning Objectives (3)How stable creatinine excretion is similar despite a decrease in

glomerular filtration rate?

How do two individuals with the same solute intake demonstrate similar urinary solute excretion despite differences in solute handling? (e.g. sodium, potassium, phosphate)

How to apply the steady-state principle to explain: e.g. (a) salt-sensitive hypertension

The principle of steady-state (i.e. when we are ‘at steady-state’) implies that input = output

The Steady-State Principle

You are what you eat

You excrete what you eat

You excrete what you add to the plasma in a given interval

Balance (i.e. in Steady-State)

Creatinine ‘Conundrum’One of two twins (with identical muscle mass) developed rapidly

progressive glomerulonephritis and now, one year later, the affected twin (still with identical muscle mass to his twin) is left with stable chronic kidney disease…let’s say…50% of his original kidney function.

Fact: at steady-state, both individuals have identical creatinine excretion.

Of two identical individuals, if one has worse renal function, how will both have identical creatinine excretion?

Creatinine ‘Conundrum’Why wouldn’t the twin with worse kidney function (i.e. lower GFR,

higher plasma creatinine) have less creatinine in the urine?

Understand: what is meant by steady-state?

Creatinine Production =

Urinary Excretion (mg/min)

Plasma CreatinineToday

Steady-State Principlex mg/dL

MeasureUrinary Cr excretion

x mg/dL

Glomerular filtration

(variable)

Plasma CreatinineYesterday x mg/dL

Plasma CreatinineLast week x mg/dL

Plasma CreatinineLast year < x mg/dL

RPGN

Creatinine ‘Conundrum’Because you observe (or often times, assume based on history)

that there is no change in the amount of a plasma solute, then at steady-state, production DOES equal excretion, INDEPENDENT of clearance

Reaching steady-state is not an active process

The kidney is not “trying” to achieve steady-state..it is passive..it is the state when we have reached equillibrium.

Creatinine ‘Conundrum’Of two identical individuals, if one developed worse renal

function, how will both have identical creatinine excretion when at steady state?

Trick: think of this in terms of the filtered load.


100 mL/min

Filtered load =

PCr * GFR

1 mg/min Urinary excretion1400 mg/day~ 1 mg/min

Renal plasma flow

How Steady-State applies to Creatinine1 mg/dL

Urinary excretion1400 mg/day~ 1 mg/min

2 mg/dL


50 mL/min

Filtered load =

↑ PCr * ↓ GFR

1 mg/min

Creatinine ‘Conundrum’The jail break analogy…for filtered load

If 10 inmates are standing at the door to the jail trying to escape, if the door is open a little, one inmate may get through even though the opening is small (akin to a decreased glomerular filtration rate).

You might imagine that if only one inmate were standing at a fairly wide-open door (akin to a normal glomerular filtration rate) trying to escape, then also, only one inmate may get through.

Solute intake = solute excretionA 45 y/o Caucasian female developed an aldosterone-producing

adenoma 1 year ago.

We know that in states of aldosterone excess, there is increased potassium secretion.

Solute intake = solute excretionFor this patient, 2 years ago we assume she didn’t have the

adenoma, but she tells us that she was eating the same amount of potassium as she is today.

We know that she has urinary potassium wasting from elevated aldosterone and has consequent hypokalemia.

How can she achieve equivalent urinary potassium excretion / day as two years ago?


Reabsorption

Secretion

Urinary K+ excretion~70 meq/day(on average)

Renal plasma flow

How Steady-State applies to other solutesK+ = 4 meq/L

Urinary K+ excretion> 70 meq/day

K+ = 4 meq/L


Reabsorption

Increased secretion

NORMAL INITIATION ofexcess aldosterone tumor (not yet at steady-state)

How Steady-State applies to other solutes

Urinary K+ excretion~70 meq/day

K+ = 2 meq/L


Reabsorption

Increased secretion

Dietary Intake =

Urinary Excretion (meq/min)

Plasma potassiumToday (one year later)

K+ = 2 meq/L

Plasma potassiumLast week K+ = 2 meq/L

Plasma potassiumSix months ago K+ = 3 meq/L

Plasma potassiumLast year K+ = 4 meq/L

↑ Aldosterone


Reabsorption

Secretion


Renal plasma flow

How Steady-State applies to other solutesK+ = 4 meq/L


K+ = 2 meq/L


Reabsorption

Increased secretion rate, but less to secrete with hypokalemia

Steady-State priorto aldosterone excess

Steady-State with aldosterone excess

Apply the Steady-State Principle to understand salt-sensitive hypertension

Salt-sensitive hypertension refers to patients whose systemic blood pressure increases with a high-sodium diet and can be treated in part by a low-sodium diet or by diuretics.

Compare: 70 y/o male who has no such propensity but also follows a high-sodium

diet.Vs. 70 y/o male who has a PROPENSITY for salt-sensitive hypertension

which is unmasked on a high-sodium diet.

Increased sodium excretion

Water follows salt

Blo

od P

ress

ure

Days

?

Sodium Intake

~150 meq/day

Blood Pressure

How Steady-State applies to hypertensionNa+

Urinary Na+ excretion~ 150 meq/day

Na+


100 mL/min

Reabsorption

ECF ECF

H2O

H2O

H2O

High Sodium Intake

~300 meq/day

↑↑ Blood Pressure

Normal response to high-sodium intakeNa+


Na+


100 mL/min

↓ Reabsorption

ECF ECF

H2O

H2O

H2O

H2O

Transient ↑↑ Blood Pressure comes back to normal bySteady-State


Water follows salt

Blo

od P

ress

ure

Days

High-sodium intake

High Sodium Intake

~300 meq/day

↑↑ Blood Pressure

Abnormal response to high-sodium intakeNa+


Na+


100 mL/min

No ↓ in Reabsorption

ECF ECF

H2O

H2O

H2O

H2O

We reach steady-state with equivalent sodium intake and output, but require a high pressure to ‘push’ the same sodium out…

For example, propensity to salt-sensitive hypertension is perhaps due to inability to fully reduce sodium reabsorption despite decrease in effector systems


Water follows salt

Blo

od P

ress

ure

Days

High-sodium intake

Learning Objectives (3)How stable creatinine excretion is similar despite a decrease in

glomerular filtration rate?

How do two individuals with the same solute intake demonstrate similar urinary excretion of that solute despite differences in solute handling? (e.g. sodium, potassium, phosphate)

How to apply the steady-state principle to explain: e.g. salt-sensitive hypertension

Also try to work through…How one reaches steady-state after an acute reduction in muscle

mass?

How does a patient with chronic kidney disease develop hyperkalemia yet have the same urinary potassium secretion as another healthy patient on an equivalent diet?

How will a person on diuretics have the same sodium excretion as another patient who doesn’t take diuretics but is on an equivalent diet?

↓ Creatinine Production

0.5 mg/min

Muscle loss

How Steady-State applies to ↓ Input1 mg/dL

Urinary excretion1400 mg/day~ 1 mg/min

1 mg/dL


100 mL/min

Filtered load = PCr * GFR

1 mg/min

(minimal reabsorption)

INITIALLY (not yet in steady-state)

↓Creatinine Production =

↓ Urinary Excretion (mg/min)

Plasma CreatinineToday

Steady-State Principle – ↓ Input 0.5 mg/dL

Urinary excretion500 mg/day

~ 0.5 mg/min

0.5 mg/dL


100 mL/min

↓ Filtered load =↓ PCr * GFR

Plasma CreatinineYesterday 0.5 mg/dL

Plasma CreatinineLast week 0.5 mg/dL

Plasma CreatininePrior to muscle loss 1 mg/dL

How Steady-State applies to ↓ Input

0 500 1000 1500 2000 25000.0

0.2

0.4

0.6

0.8

1.0

1.2

Time (minutes)

Pla

sma

Cre

atin

ine

(mg/

dL)

How Steady-State applies to ↑ K in CKD


K+ = 6.0 meq/L

Glomerular filtration(~ = filtered load)

Reabsorption

Decreased secretion

Dietary Intake =

Urinary Excretion (meq/min)

Plasma potassiumToday (one year later)

K+ = 6.0 meq/L

Plasma potassiumLast week K+ = 6.0 meq/L

Plasma potassiumSix months ago K+ = 5.0 meq/L

Plasma potassiumLast year K+ = 4 meq/L

↑ CKD

Sodium Intake

~150 meq/day

Steady-State with diuretic useNa+

Urinary Na+ excretion> 150 meq/day

Na+


100 mL/min

↓ Reabsorption

ECF ECF

H2O

H2O

H2O

Transient ↑ urinary sodium excretion before reachingSteady-State

Sodium Intake

~150 meq/day

Steady-State with diuretic useNa+


Na+


100 mL/min

↓ Reabsorption

ECF ECF

H2O

H2O

H2O

In Steady-State

The End

application of the steady-state principle vivek bhalla, md division of nephrology stanford...

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