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Renal Pathophysiology |
For reference: [NephronMap] A very useful, printable schema of the nephron, courtesy of Daniel K. Moon, P&S 2010.
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These notes were written by Dr Donald Landry and edited by him and Q. Al-Awqati. They are not meant to replace your syllabus.
Acute Tubular Necrosis
Case 2, question d.
Indications CysticFibrosis
with
GI bleed with
for dialysis nonoliguric
ATN
hypotension
?2o to
gentamicin
and acute renal failure
1. Volume non
oliguric
oliguric -
easier to manage
fluids
volume overload more likely
2. Acidosis moderate
acidosis
due
same mechanism but in
to low
GFR
addition perhaps also lactic
with "little
opportunity
acidosis due to hypotension
for H+ to be added to
urine" - p.80
3. K+
less of a problem because
of often
hyperkalemic
maintained urine volume
because of oliguria
4. Uremia BUN/Creatinine ratio normal high BUN/Creatinine ratio
Causes of High BUN/Creatinine ratio
Creatinine reflects the GFR while BUN while reflecting GFR also reflects protein
metabolism. Thus the causes of high BUN/Cr ratio include; high protein diet;
blood in the GI tract; and high catabolic state (i.e. fever, sepsis)
Uremia is the syndrome produced by renal failure and is associated with anemia, platelet dysfunction and bleeding diathesis, pericarditis, encephalopathy, neuropathy. The syndrome is not due to high BUN per se; rather it reflects a composite of all things that the kidney doe; including its regulation of fluid and electrolytes, its hormonal function as well as the excretion of poorly characterized "toxins" that are the product of protein metabolism
Hypertension
Evaluation for HTN:
1. Evaluate for chronic damage
Eyes
Examine for hypertensive retinopathy
Cardiovascular Left Ventricular
Hypertrophy by Chest X ray, EKG or Echocardiogram
Kidneys
increased Creatinine
Peripheral Vasculature decreased pulses, loss of cutaneous
adnexal structures
2. Evaluate for acute hypertensive crisis - malignant Hypertension
brain: encephalopathy (? in mental status, asterixis, etc.)
eyes: papilledema
cardiothoracic: acute CHF pulmonary edema, ischemic changes on EKG
kidney: hematuria, acutely increasing creatinine.
3. Evaluation for Secondary causes of Hypertension
renal failure check serum Cr
Coarctation check BP in upper and lower extremities, look
for
rib notching on Chest XRay
Primary Hyperaldosteronism caused by an adrenal tumor check for
low serum K+ & high HCO3 and low plasma renin in the fact of low salt
intake
Reninoma check for tumor (very rare)
Renal Artery Stenosis High renin; listen for renal artery bruit (not a
very specific finding especially in the elderly); renal scan or renal
arteriogram & selective renal vein renins
Cushing's Syndrome: physical exam, should show signs and symptoms
of glucorticoid excess labs as in Primary Hyperladosteronism. If
suggestive
then check cortisol levels
Pheochromocytoma history of paroxysms of HTN, tremor, pallor
24 hr urine for catecholamine metabolites(VMA, metanephrine) and check
serum for catecholamines
Note: The above is simplified but I wanted you to have a feel for relating the
pathophysiology to the care of a patient.
Regulation of the Volume of the Body Fluids
Most Important Idea to remember is that the volume of the body fluids is a
reflection of the Sodium Content not the Sodium Concentration.
Therefore start your analysis always by finding out if the Sodium Intake
matches the Sodium Output.
Remember Na Intake diet; I.V.
Na Output urine; gi (stools or fistula), sweat
Volume status is determined by physical examination.
ECF volume depletion: dry mouth, decreased axillary sweat,
decreased skin turgor
Intravascular volume depletion:
mild
tachycardia on standing
moderate orthostatic hypotension
severe
actual hypotension
Laboratory correlates: hemoconcentration, increased serum
albumin, increased uric acid, increased BUN (and if severe
increase Cr 2o to decrease GFR), decreased urine sodium
concentration
ECF volume Expansion: We can retain up to 3 liters of saline without any signs or symptoms. Retention of greater amounts leads to peripheral edema and ascites
Intravascular volume expansion: hypertension and/or the
overload patterns below
"left-sided overload" SOB, dyspnea on exertion, orthopnea,
PND, pulmonary edema with rales on physical examination
" right-sided overload" pedal edema, increased liver size (and
increased LFT's), hepatojugular reflux, ascites, increased
jugular venous distention
Laboratory correlates: hemodilution, decreased serum albumin, hypoxia on arterial blood gas, and peripheral vascular congestion on chest x-ray
Tonicity Regulation of the Tonicity of the Body Fluids
Most Important Idea to remember is that the Tonicity of the body fluids is a
reflection of its Water Content. This is measured most explicitly by the
Osmolality. However, an excellent surrogate marker is the Serum
Sodium Concentration. Hyponatremia reflects high water content (more
dilute solutes like Na) and Hypernatremia reflects low water content (more
concentrated solutes like Na).
Therefore start your analysis always by finding out if the Water Intake matches
the Water Output.
Remember Water Intake diet; I.V.
Water Output urine; gi (vomiting, diarrhea or
fistula), sweat
The daily fluid in-take is hypoosmolar
In order to cope with this water load a large volume of dilute urine must be
generated
1. A "large" volume requires the there not be increased proximal
tabular reabsorption of salte and H2O(as there is in volume depletion, CHF
etc.).
2. Dilute urine requires that ADH not act on the distal nephron. [Also
diuretics which ? UNa preent a dilute urine.]
3. Increased oral intake worsens the problem. [AII increases thirst & AII
is increased in the situations lsited in 1.]
Evaluation of hyponatremia
First, exclude pseudohyponatremia due to hyperlipemia or hyperproteinemia
Check serum osmolality just to be sure that this is not a hyperosmolar state
that has depressed serum sodium - for example hyperglycemia - then evaluate
Hyponatremia from whatever cause has only one physiological cause: Water
Intake must have been greater than Water Excretion. Low Na concentration
reflects dilution and not necessarily a Na deficit.
Check Volume status. Hyponatremia can exist in states of Volume Depletion,
Hyponatremia in ECF Volume Depletion
body weight likely to be lower than previously
pulse and blood pressure might show orthostatic changes
No edema
True Intravascular volume actually low
Causes include; vomiting or diarrhea or excessive use of laxatives, excess use
of diuretics; osmotic diuresis (due to hyperglycemia in untreated diabetes
mellitus)
"3rd Space"
The Urine Na is often Low (i.e. below 20 mEq/L) except, of course when the
patient is taking a diuretic.
Pathophysiology Whatever the state of volume,
hyponatremia can only develop if the patient's water intake is greater than
excretion.
Decreased Volume increases ADH release
Low volume increases renin, and angiotensin II levels. That causes increases in
filtration fraction and increased proximal reabsorption. Therefore amount
delivered to distal diluting segment is reduced. Hence total amount of dilute
urine that can be generated is low.
Treatment Isotonic Saline
Hyponatremia when theECF Volume is Normal
body weight likely to be same, no orthostatic changes
One rare cause is Psychogenic Polydipsia where water intake is greater than the
kidney's ability to excrete dilute urine (about 20 Liters /day)
Common Cause include decreased "Effective" Plasma Volume where
there is arterial underfilling. This is seen in Heart Failure, Cirrhosis and
Nephrotic Syndrome. Such patientsoften have Edema. Other causes include
hypothyroidism, hypopituitarism and reduced glucocorticoid activity as in
Addison's disease.
Urine Na is often low
Pathophysiology Decreased Effective Volume also
increases ADH release by non-osmotic stimuli.
Low Effective volume and decreased arterial filling increases renin, and
angiotensin II levels. That causes increases in filtration fraction and
increased proximal reabsorption. Therefore amount delivered to distal diluting
segment is reduced. Hence total amount of dilute urine that can be generated is
low.
Treatment Water Restriction
Hyponatremia when theECF Volume is High
Syndrome of inappropriate ADH (same as infused ADH):
seen in many conditions; see Table in your syllabus.
Urine Na is often high (if patient's salt intake in maintained.
No edema because you can retain up to 3 L of saline without getting edema.
Pathphysiology
1) free H2O is retained due to ADH induced increased H2O permeability at the
collecting duct.
2) The retained H2O dilutes the total body water - a portion of this is the
intravascular volume, hence serum Na is decreased (diluted) and the volume
increases.
3) The increased intravascular volume suppresses sympathetic outflow,
suppresses renin/AII and activates ANF
4) The increased intravascular volume and suppressed AII decreases
aldosterone secretion. Therefore less Na is reabsorbed distally.
5) As a result of 3 & 4 urine Na is high
Etiology of Hypernatremia
H2O intake has not kept up with output. Remember that thirst should have
prevented this. Identify why it has not.
1. decreased H2O input, e.g. inability to reach H2O (ex: coma) or 2o to
vomiting
2. increased H2O output
Non renal - 1. sweat (especially with fever)
Renal 2. osmotic diuresis (eg: hyperglycemia); See notes for details -
the glucose particles cannot be reabsorbed; H2O > Na is lost with the
excretion of the particle
3. diabetes insipidus
- central - no ADH; Tumor, head trauma, etc
- nephrogenic - insensitivity to ADH 2o to: low K+ high
prostaglandins effect on cAmp, decreased Na reaborption in thick ascending limb
high CA++ decreases effect of adenylate cyclase
ETOH inhibitor of ADH release
Lithium inhibits adenylate cyclase
amyloidosis direct effect on collecting duct
drug induced - demeclocycline
or congenital
Hypernatremia decreased H2O content relative to Na+ not
necessarily Na excess. Serum sodium level reflects H2O handling.
Glomerular Disease
- Nephritic Syndrome
RBC casts and/or dysmorphic RBC's
Proteinuria may or may not be nephrotic range
Pathophysiology: "primary" salt retention with edema and hypertension
- Nephrotic Syndrome
24 hr urine protein > 3.5 g [but first Rule Out multiple myeloma]
Pathophysiology of edema either 2o to decreased arterial falling or to primary
salt retention
Urinary protein content is a sufficient criterion for diagnosis but true
syndrome includes low Serum albumin, edema, high serum cholesterol. Also
a hypercoaguable state or Fanconi's syndrome may be present.
- Isolated urinary abnormalities
proteinuria < nephrotic range; or hematuria or both
If pure nephrotic syndrome (benign urinary sediment) is present, then attempt
to differentiate secondary NS - due to drugs, tumor etc - from idiopathic NS;
bx usually required; serum creatinine may or may not be ?; if ?'ing then
usually very slowly unless a special insult such as HIV nephropathy is present.
If a nephritic (or active) urinary sediment is present serum creatinine may
increase over course of weeks.
? serum complement ? anti GBM Ab ? anti
neutrophil
cytoplasmic antibody
re immune complex re Goodpasture or re Wegners
or isolated renal or Microscopic PAN
variant
If complement is low ? post infectious check ASLO titer
check for SLE check ANA
For mixed cryogobulinemia check cryoglobulins
renal biopsy required for the diagnosis of idiopathic membranoproliferative
Potassium
In K balance, you should remember that most of the total body K is
intracellular, hence serum K is only a gross measure of K content. Therefore,
you have to think about K intake, K excretion and re-distribution
of K between intracellular and extracellular spaces.
· Hypokalemia
A) Low Input
Dietary insufficiency (uncommon)
B) High output (renal)
i) Primary Hyperaldosteronism (or Cushings with glucocorticoids
binding to aldosterone receptor)
ii) Alkalosis (K+ enters cell) causing increased cellular K+ in distal
tubular cells leading to K+ secretion)
iii) high urine flow in distal (salt & H2O not just H2O as in D.I.)
Osmotic diuretics - glucose, mannitol;
loop diuretics-lasix; also HCTZ (non-loop);
NaHCO3 wasting in distal or proximal RTA.
Note: volume depletion causes increased aldo but urine volume and distal
delivery of Na re decreased; therefore K+ losses are not excessive.
However in (1) primary hyperaldosteronism, urine Na+ and volume are in steady
state and likely not low i.e. increased distal Na reabsorption increased urine
volume due to low AII and low FF causing decreased prox reab and
increased distal delivery which eventually overcomes even the aldo
stimulated distal Na+ reabsorption and in (2) volume depletion with
diuretics. Aldo is increased but urine output and distal delivery of Na
is maintained by diuretics. And in each of these cases, perhaps more
important then flow per se, is the delivery of Na to the distal nephron - Na
reabsorption generates a negative membrane potential that drives K+ secretion.
C) Increased Non Renal Output
i) Sweat
ii) diarrhea, villus adenoma, laxative abuse, etc.
D) cellular shifts -
alkalosis
(K+ moves into cells) - Rx with glucose & insulin or with glucose alone
in a non-diabetic
- Rx with ? agonist
Note: often several mechanisms operate simultaneously for example: Type II
diabetic with high glucose, nausea & vomiting:
1) vomiting with volume depletion and high aldo
2) vomiting with increased H+ loss causing alkalosis
3) high glucose causing osmotic diuresis with high urine flow & increased
distal delivery of Na
Hyperkalemia
A) Increased Input alone is rarely a cause
B) Decreased Output
i) low urine volume such as in acute tubular necrosis with oligiuria
[Simple volume depletion has low urine volume but high aldosterone; hence
we usually see normal K+. This is true for "effective" vol
depletion such as CHF however if Rx with aldosterone inhibitor such as
spironolactone ? see marked hyperkalemia]
ii) acidosis (decreased cellular K+ decreased distal tubular cell K+ causing decreased K+ secretion)
iii) hypoaldosteronism
- hyporenin hypoaldo (remember type IV RTA) in
diabetes mellitus
- adrenal insufficiency
C) Cellular Shifts
i) acidosis (K+ out of cells)
ii) B blocker
iii) digoxin intoxication
D) Ultimate Cellular Shift
i) hemolysis
ii) rhabdomyolysis
E) Pseudohyperkalemia
hemolysis of sample
high plts (> 800,000)
high WBC (>50,000)
Acid Base Abnormalities
Metabolic Alkalosis
A) Generation of alkali
I Non renal
i. vomiting or gastric aspiration (H+ loss)
ii. infusion of sodium salt of carboxylic acid (ex Na
lactate) that is
metabolized to NaHCO3
II Renal
i. Diuretics and volume depletion
ii Primary hyperaldosteronism
iii Primary hyper glucocorticoidism (Cushing's) (also binds to aldo receptor)
iv other (there is renal generation of HCO3 but not alkalosis until
respiratory function improves; therefore requires a maintenance mechanism)
v Sudden Correction of chronic respiratory acidosis that exposes the
renal retention of HCO3-.
B) Maintenance of Alkalosis
Alkalosis is largely maintained by the Kidney where most of
the causes are associated with an increased H secretion; i.e. increased HCO3
formation which serves to maintain the alkalosis.
i volume depletion increases proximal & distal HCO3-reabsorption
ii decreased GFR (less HCO3- is filtered - perhaps important in some cases of
volume depletion)
iii low K+ - increased prox reabsorption of HCO3.
There are some non renal causes of maintenance
Metabolic Acidosis
Two basic conditions:
a) HCO3 has been lost directly, or inadequately generated by the
kidney
b) an increase in the acid load has titrated body fluid HCO3
A-H + HCO3-----> A + H2CO3 -----> H2O + CO2)
The situation in (a) gives rise to a normal anion gap (but see renal failure #1 & #3 below),whereas (b) results in an increased anion gap - unless the increased acid is HCl or its equivalent such as arginine HCl.
NORMAL ANION GAP
Renal:
i renal HCO3 loss: distal RTA, proximal RTA, carbonic anhydrase
inhibitors ii inadequate HCO3 generation: Type 4 RTA (hyporenin hypoaldo)
results in high K+ which decreases NH3 synthesis and reduces titrable acid
excretion leading to low HCO3 generation by the tubule. Also, see renal failure
#2
Non renal:
i. GI HCO3 loss: diarrhea, bile drainage etc.
ii Administration of HCl, arginine HCl, etc.
INCREASED ANION GAP
1. lactic acidosis - metabolic poisoning,
hypoxia/hypoperfusion
2. ketoacidosis - DKA, alcoholic ketoacidosis
3. poisoning with ethylene glycol, methanol, paraldehyde
4. renal failure
renal failure deserves special mention
i. acute renal failure results in decreased titrable acid excretion,
retention of anions and a high anion gap
ii moderate chronic renal failure - with a CrCl < 20-25 cc/min - the ability of the remaining nephrons to increase NH3 is exceeded and acidosis results. Anions are not noticeably retained and the Anion Gap is nl. Compare to Type 4 RTA.
iii. Severe chronic renal failure - CrCl < 15
cc/min - at this point the ability of the kidney to excrete anions is exceeded
and the acidosis becomes one of high AG.
Approach to the patient when Arterial Blood Gases demonstrates metabolic
acidosis
Determine anion gap
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Normal |
High |