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