Renal Pathphysiology II
Regulation of Plasma Composition
Nancy Long SieberNovember 28, 2011
Measurment Normal Value Comments Solute Concentration Osmolarity 295 mOsm/L
Osmolar gap <10 mOsm/L Difference b/w measured and calculated osmolarity. A larger gap indicates presence of abnormal substances in blood, eg: toxicity
Ion Concentrations: Na+ 135 - 145 mEq/L Main component of plasma
osmolarity K+ 3.5 – 4.5 mEq/L Altered by diabetes, excess
aldosterone, diuretic use. Cl- 95 – 105 mEq/L Tends to follow pattern of Na+
absorption from renal tubule.
Ca++ 2.1 mmol/L Much is bound to protein. Not tightly regulated by kidneys – GI absorption is more impt.
Normal Plasma Values
Measurment Normal Value
Comments
Plasma Proteins & Amino acids Albumin 3.4 – 5.4
g/dLIndicates liver damage, protein loss in urine (due to failure of glomerular barrier) or protein malnutrition/malabsorption
Alkaline phosphatase
44-147 IU/L
Indicates liver damage or bone diseaseHigher in pregnant women, growing children. Used to monitor liver toxicity in people using drugs with hepatotoxic side effects. Other liver enzymes may also be measured,
Homocysteine 0-10 umol/L
Indicates increased risk of heart disease
Indicators of glucose handling: Glucose 65 – 110
mg/dL High in people with diabetes mellitus. Lack of insulin prevents glucose from entering cells.
A1C (glycolated hemoglobin)
4-6% Fraction of hemoglobin molecules that have glucose attached. A long-term measure of diabetes management.
Normal Plasma Values, Continued
Renal Blood Flow and FunctionCreatinine 0.8 – 1.5 mg/dL
Blood urea nitrogen (BUN)
8 – 25 mg/dL Urea is a breakdown product of protein metabolism. It is produced in the liver, and is freely filtered by the kidneys. It accumulates in the blood when there is insufficient blood flow to the kidneys, or when kidneys are failing. Low BUN can indicate liver disease.
Acid-Base Status
pH 7.4
HCO3 - 24 – 32 mEq/L
Normal Plasma Values, Continued
Measurment Normal Value Comments
Measurment Typical Value CommentsUrine color (Urobilins) Straw yellow Darker in morning – more concentratedUrine volume 1-2 L per day Highly variableOsmolarity – random sample
50-1400 mOsm/L Depends on fluid intake – reflects levels of ADH
Osmolarity after 12-14 h fluid restriction
>850 mOsm/L
Protein 0 - trace Presence of protein indicates failure of glomerular barrier
Ketone bodies 0 Breakdown product of fat metabolism. Presence indicates problem with carbohydrate metabolism (eg: diabetes mellitis) or prolonged fasting
Glucose 0 Presence indicates diabetes mellitisCreatinine 500 – 2000
mg/dayUsed to estimate GFR. Filtered but only a tiny bit is secreted, not reabsorbed by renal tubules.
White blood cells, pus 0 Indicates urinary tract or renal infectionRed blood cells, hemoglobin
0 Infection or injury in urinary tract or kidney, kidney stones or other obstruction, etc.
Bilirubin 0 Breakdown product of hemoglobin, which is normally excreted into the GI tract with bile via the bile duct. Presence in urine indicates liver or gallbladder (storage of bile) problems. Causes darkening of urine.
pH 4.8 – 7.5 Depends on diet (more acidic in meat eaters). Can also reflect metabolic or respiratory acid-base disorders
Urine Composition
Osmolarity
Plasma Osmolarity
Posm = 2 x [Na+(mEq/L)]p + [glucose(mg/dl)]/18 + [urea (mg/dl)]/2.8
• The difference between measured and calculated plasma osmolarity is the result of unmeasured osmoles.
• These include potassium, chloride and proteins, but they account for very little of the total osmolarity.
Plasma Osmolarity Values:
Posm = 2 x [Na+(mEq/L)]p + [glucose(mg/dl)]/18 + [urea (mg/dl)]/2.8
Posm = 2 x [140 mEq/L)]p + [90 (mg/dl)]/18 + [14 (mg/dl)]/2.8
280 + 5 + 5 = about 290 mOsm/kg
Sodium is responsible for about 97% of plasma osmolarity.
Conditions in which plasma Na+ is low, but osmolarity is normal
• Usually there is another solute present.• Body responds to increase osmolarity by
increasing ADH release, and water retention. This dilutes the sodium.
• Eg: High glucose in diabetic patient
• Eg: Ethylene glycol poisoning
www2.kumc.edu/ki/physiology/course/figures.htm
True hypoosmolarity (low sodium and low osmolarity)
• Could be due to :– Problems with ability to sense osmolarity, or to
changes in set point for osmolarity– Alterations in thirst mechanism– Problems with ADH release– Problems with renal response to ADH– Drinking too much water before or during exercise
To consider the possible causes of hypoosmolarity, consider the components of the negative
feedback loop for osmoregulation.
• Sensor: osmoreceptors
• Set point: normal value = about 295 mOsm/L
• Responses: – Thirst (decreased in response to hypoosmolarity)– ADH release (decreased in response to hypoosmolarity)
ADHrelease
Plasma osmolarity (sOsm/L)
280 290 300 310 320
progesterone
Hypo-osmolarity Example: Pregnancy Lower setpoint for osmolarity - ADH release and thirst occur at a lower than normal osmolarity.
Vasopressin = ADH
Hypo-osmolarityexample: Psychogenic Polydipsia
Hypo-osmolarity example: Loss of plasma volume
ADH release is triggered by decrease in plasma volume rather than an increase in osmolarity.
Note that ADH is an effector for regulating two different regulated variables.
Hypo-osmolarity Example:Fluid loss to interstitium
• Example: Cirrhosis of the liver– Damage to liver interferes with protein production– Fluid leaks out of capillaries due to shift in Starling
forces– Fluid accumulates in abdomen – ascites – Also: portal hypertension increases hydrostatic
pressure, injury and inflammation increases permeability to proteins, exacerbating the condition.
Hyperosmolarity of plasma due to high sodium conc.
• Can be caused by:– Administration of sodium salts– Loss of hypotonic fluids (vomiting diarrhea,
sweating)– Extrarenal fluid loss (eg: increased ventilation as
occurs in fever)– Excessive renal water loss (inability to secrete or
respond to ADH)
Example: Diabetes insipidus
• Can be due to lack of ADH production, or in the case of nephrogenic diabetes insipidus, lack of ability to generate an osmotic gradient for water reabsorption
• Results in loss of large volume of hypotonic urine
Potassium
Potassium Regulation
• Most (55%) of the filtered potassium is reabsorbed in the proximal tubule, another 30% is absorbed in the loop of Henle.
• Depending on diet, potassium may be reabsorbed or secreted in the distal convoluted tubule and the cortical collecting duct.
Renal handling of potassium
Regulation of potassium secretion
• Na+/K+/ATPase A high K+ diet enhances update of K+ into the principal cells (the ones that line the tubule)
• Aldosterone increases K+ uptake into the principal cells (via Na+/K+/ATPase), and makes the luminal membrane more permeable to K+
• K+ secretion is flow dependent – high urine production can lead to K+ deficiency.
K+
Na+
K+
Na+
insulinadrenalinaldosterone
K+
K+acidosisincreased osmolaritycell injury
Hyperkalemia in diabetes mellitus
Aldosterone altersthe expression of this enzyme
Glucose
•From: Physiology of the Kidney and Body Fluids” by R.F. Pitts.
•From: Physiology of the Kidney and Body Fluids” by R.F. Pitts.
↑plasma glucose
↑filtered glucose
Tm exceeded
glucose remains in tubules
H2O retained osmotically
increased urine volume
if not replaced by drinking, blood volume decreases
Increased urine volume in diabetes mellitus
Example: Untreated diabetes mellitus (assuming no renal damage)Increased plasma glucose
Increase filtered glucose
Tm exceeded
Glucose remains in tubules
Water retained in tubules osmotically
Increased urine volume
Blood volume decreases (if not replaced by drinking)
Decreased blood pressure (by Frank-Starling mechanism)
Increased urine volume in diabetes mellitus
Acid-Base Balance
Alterations in plasma H+ concentrations can be potentially life-threatening
Condition [H+] pH Significance(nmol/L)
Acidosis >100 <7.0 life-threatening50-80 7.1-7.3 clinically signif.
Normal 40+2 7.4+0.02 normal
Alkalosis 25-30 7.4-7.6 clinically signif.<20 >7.7 life-threatening
from Clinical Detective Stories, Halperin and Rolleston. Portland Press 1993.)
Alterations in plasma H+ concentration can influence potassium balance
• Acidosis (excessive H+) causes K+ to move out of cells
• Alkalosis (insufficient H+) causes K+ to move into cells.
• Mechanisms of these interactions is not clear.
• Diabetics are at risk for hyperkalemia (plasma K+ levels too high) since they tend to develop acidosis as a result of the production of ketoacids.
Hydrogen Ion Balance
• We gain hydrogen ion through diet and metabolism– Meat eaters tend to produce more acid
• Dietary hydrogen ion is consumed through metabolism, and lost through the expiration of CO2, and excreted in the urine.– Meat eaters produce a more acidic urine
Hydrogen Ion Balance is Maintained by Buffers
• Most important is Bicarbonate (HCO3-)
• Also:– Proteins– Phosphate – NH4
+
http://www2.kumc.edu/ki/physiology/course/images/fig9_8.gif
How does hydrogen ion concentration get out of balance?
• There are two basic kinds of problems– Acidosis– Alkalosis
• There are two basic causes of these problems:– Metabolic– Respiratory
• In addition, there are metabolic and respiratory compensations for imbalances in either system.
Acid-Base Imbalances Involve Shifts in This Equation:
CO2 + H2O H2CO3 HCO3- + H+
Normal Values: H+ = 0.00004 mmol/LHCO3
- = 24 mmol/L
Acidosis
• Metabolic – results from excess acid production or loss of alkaline fluid– High lactic acid production during exercise– Prolonged diarrhea
• Respiratory – results from hypoventilation– Injury that makes ventilation painful– Lung disease
Compensation for Acidosis
• Metabolic Acidosis– Increased ventilation
• Respiratory or Metabolic Acidosis– Increased excretion of H + (requires a phosphate
group, which is in limited supply– Increased NH4
+ production
Alkalosis
• Metabolic – results from prolonged vomiting, which causes the loss of an acid-containing fluid, or from the ingestion of alkali fluid
• Respiratory – results from hyperventilation
Compensation for Alkalosis
• Metabolic Alkalosis– Sometimes results in decreased ventilation, but
this is a relatively small response
• Respiratory or Metabolic Alkalosis– Increased renal excretion of bicarbonate– NH4
+ production and excretion are inhibited