1. Renal Pathphysiology II Regulation of Plasma Composition Nancy Long Sieber November 28, 2011

2. MeasurmentNormal ValueComments Solute Concentration Osmolarity295 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/LMuch is bound to protein. Not tightly regulated by kidneys – GI absorption is more impt. Normal Plasma Values

3. Measurment Normal Value Comments Plasma Proteins & Amino acids Albumin 3.4 – 5.4 g/dL Indicates 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 disease Higher 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

4. Renal Blood Flow and Function Creatinine0.8 – 1.5 mg/dL Blood urea nitrogen (BUN) 8 – 25 mg/dLUrea 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 pH7.4 HCO 3 - 24 – 32 mEq/L Normal Plasma Values, Continued MeasurmentNormal ValueComments

5. MeasurmentTypical ValueComments Urine color (Urobilins)Straw yellowDarker in morning – more concentrated Urine volume1-2 L per dayHighly variable Osmolarity – random sample 50-1400 mOsm/LDepends on fluid intake – reflects levels of ADH Osmolarity after 12-14 h fluid restriction >850 mOsm/L Protein0 - tracePresence of protein indicates failure of glomerular barrier Ketone bodies0Breakdown product of fat metabolism. Presence indicates problem with carbohydrate metabolism (eg: diabetes mellitis) or prolonged fasting Glucose0Presence indicates diabetes mellitis Creatinine500 – 2000 mg/day Used to estimate GFR. Filtered but only a tiny bit is secreted, not reabsorbed by renal tubules. White blood cells, pus0Indicates urinary tract or renal infection Red blood cells, hemoglobin 0Infection or injury in urinary tract or kidney, kidney stones or other obstruction, etc. Bilirubin0Breakdown 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. pH4.8 – 7.5Depends on diet (more acidic in meat eaters). Can also reflect metabolic or respiratory acid-base disorders Urine Composition

6. Osmolarity

7. Plasma Osmolarity P osm = 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.

8. Plasma Osmolarity Values: P osm = 2 x [Na + (mEq/L)] p + [glucose(mg/dl)]/18 + [urea (mg/dl)]/2.8 P osm = 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.

9. 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

10. www2.kumc.edu/ki/physiology/course/figures.htm

11. 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

12. 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)

13. ADH release 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.

14. Vasopressin = ADH Hypo-osmolarity example: Psychogenic Polydipsia

15. 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.

16. 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.

17. 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)

18. 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

19. Potassium

20. 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.

21. Renal handling of potassium

22. 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.

24. K + Na + K + Na + insulin adrenalin aldosterone K+K+ K+K+ acidosis increased osmolarity cell injury Hyperkalemia in diabetes mellitus

25. Aldosterone alters the expression of this enzyme

28. Glucose

29. From: Physiology of the Kidney and Body Fluids” by R.F. Pitts.

31. ↑plasma glucose  ↑filtered glucose  Tm exceeded  glucose remains in tubules  H 2 O retained osmotically  increased urine volume  if not replaced by drinking, blood volume decreases Increased urine volume in diabetes mellitus

32. 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

33. Acid-Base Balance

34. Alterations in plasma H+ concentrations can be potentially life-threatening Condition [H+]pHSignificance (nmol/L) Acidosis>100<7.0life-threatening 50-807.1-7.3clinically signif. Normal40+2 7.4+0.02normal Alkalosis25-307.4-7.6clinically signif. 7.7life-threatening from Clinical Detective Stories, Halperin and Rolleston. Portland Press 1993.)

35. 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.

36. 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 CO 2, and excreted in the urine. – Meat eaters produce a more acidic urine

37. Hydrogen Ion Balance is Maintained by Buffers Most important is Bicarbonate (HCO 3 - ) Also: – Proteins – Phosphate – NH 4 +

38. http://www2.kumc.edu/ki/physiology/course/images/fig9_8.gif

39. 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.

40. Acid-Base Imbalances Involve Shifts in This Equation: CO 2 + H 2 O  H 2 CO 3  HCO 3 - + H + Normal Values: H+ = 0.00004 mmol/L HCO 3 - = 24 mmol/L

41. 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

42. 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 NH 4 + production

43. 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

44. 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 – NH 4 + production and excretion are inhibited