Uremic Toxicity

1. Uremic Toxicity Kopple J. D. and Massry S. D. :Nutritional Management of Renal Disease, p97-190 營養師:賴美足 日 期:92.08.15

2. Uremia-1 • Greek words : urine + blood = uremia • Uremia is the retention of excessive by products of protein metabolism in the blood and the toxic condition produced thereby.

3. Uremia-2 • Uremia is a toxic syndrome caused by severe glomerular insufficiency, associated with disturbances in tubular and endocrine functions of the kidney. It is characterized by retention of toxic metabolites, associated with changes in volume and electrolyte composition of the body fluids and excess or deficiency of various hormones.

4. Uremic symptoms and signs Table 5.1. • Central nervous system • Peripheral nerves • Gastrointestinal tract • Hematologic and immunologic • Cardiovascular system • Respiratory system • Skin • Musculoskeletal system • Endocrine and metabolic changes

5. Toxic effects of uremic plasma • There is evidence that a variety of disturbances, such as anemia, immunologic deficiency, bleeding tendency, disorders of carbohydrate and lipid metabolism, and various membrane transport disturbances.

6. Definition of a uremic toxin • Plasma and /or tissue concentration of the compound should be higher in uremic patients. • High concentrations The compound should be chemical identified, specific and accurate quantitative analysis • should be related to specific uremic symptoms and disappear when the concentration is reduced. • Studying toxicity of the compound , the concentration shoul be compartable to those found in the body fluids and/or tissues of uremic patients.

7. Factors that influence uremic toxicity • Dialysis treatment • Small, middle-sized, and large moleules

8. Factors that influence uremic toxicity-1 Dialysis treatment • The aimof dialysis treatment is to normalize the volume and composition of the body fluids. • Efficacy of dialysis: molecular size, degree of plasma protein binding

9. Factors that influence uremic toxicity-2 Small, middle-sized, and large moleules • Size: Small : < 500 ( or 350 ) Da Middle : 500 ~ 5,000 Da Large : > 5,000 Da • Protein binding • Protein intake • Intestinal bacterial flora

10. Toxicity of inorganic substances in uremia • Water • Sodium • Potassium • Hydrogen ions • Magnesium • Phosphate • Sulfate • Trace elements

11. Toxicity of inorganic substances in uremia Water • Water overload: isotonic (edematous conditions), hypotonic (water intoxication) • Cause: inappropriate thirst or iatrogenic influsion of excess fluid. • Water excess: edema and heart failure. • Water intoxication: mental confusion, restlessness, twitching, muscle cramps, convulsions, coma.

12. Toxicity of inorganic substances in uremia Sodium • Sodium retention • Hypertension • Pulmonary edema • Heart failure • Peripheral edema

13. Toxicity of inorganic substances in uremia Potassium • Hyperkalemia : oral intake parental administration endogenous catabolism • Metabolic acidosis : K moves out of the cells as pH decreases. • Cardiovascular : ECG change ventricular fibrillation cardiac arrest

14. Toxicity of inorganic substances in uremia Hydrogen ions • Metabolic acidosis (common feature of renal failure) presented with elevated concentration of hydrogen ions. • Central nervous system disorder, hyperventilation, hyperkalemia, abnormality in energy metabolism, and dissolution of bone.

15. Toxicity of inorganic substances in uremia Magnesium • Hyper~ Vomiting Malaise Hypotension Decreased reflexes Arrhythmias • Cardiac arrest be observed after Mg salt

16. Toxicity of inorganic substances in uremia Phosphate • Hyper~ • When the GFR falls below 25% of normal • Calcium phosphate deposits in organs and tissues ( renal calcification ) • Treatment : oral calcium carbonate ( low – protein diet )

17. Toxicity of inorganic substances in uremia Sulfate • Unstable calcium sulfate complexes deposited in the skin could be a significant factor in dialysis related pruritus.

18. Toxicity of inorganic substances in uremia Trace elements • Heavy metals and other trace elements. • Accumulation in uremic patients: reduce renal excretion, excess uptake from dialysis fluid,dialysis equipment,or oral medication. • High concentration of aluminum, arsenic, chromium, copper, cobalt, silicon ..etc.

19. Organic compounds of Low molecular weight • Urea • Creatinine • Guanidines (other than creatinine) • Methylguanidine • Guanidinosuccinic Acid (GSA) • Methylated Arginine Metabolites • Other guanidines • Products of Nucleic Acid Metabolism

20. Organic compounds of Low molecular weight Urea (1) • The most important end product of nitrogen metabolism in mammals and acount for 85% of the urinary nitrogen excretion. • Blood concentration: glomerular filtration rate, nitrogen intake, balance between endogenous protein synthesis and breakdown.

21. Organic compounds of Low molecular weight Urea(2) • In hemodialysis patients: low serum urea nitrogen level (low protein intake), increase risk of death; Excess high of serum urea nitrogen level (underdialysis), increase mortality. • Estimate adequacy of dialysis (small molecular) : Urea clearance × length of dialysis ÷ distribution volume of urea.

22. Organic compounds of Low molecular weight Urea(3) • High concentration: headache, fatigue, nausea, vomiting, glucose intolerance, and bleeding. • The most severe uremic GI, CV, mental and neurologic changes were not seen. • Considered “mild” uremic toxin . • Role in the pathophysiology of uremia is not well defined.

23. Organic compounds of Low molecular weight Creatine(1) • The major guanidine compound retained in patients with diminished glomerular filtration rate. • Produce from the creatine pool in skeletal muscle and some extent from exogenous creatine present in meat. • Routinely determined in plasma or serum as a measure of impairment of renal function.

24. Organic compounds of Low molecular weight Creatinine(2) • In general , toxic effects in vitro of creatininee only been observed at concentration much higher than those found in uremic patients.

25. Organic compounds of Low molecular weight Other guanidines • The concentrations of various guanidine compounds are higher in uremic patients. • Some toxic in vitro effects seem to have been obtained at concentrations similar to those in uremic body fluids. • Most in vitro and in vivo toxis effects have been observed at much higher concentrations than are found in uremic patients • The role of guanidines as uremic toxins is stillm not well defined.

26. Product of Nucleic Acid Metabolism • Uric acid and other purine derivatives • Cyclic AMP • Pyridine derivatives • Amino acids, dipeptides, and tripeptides • Sulfur amino acids • Aliphatic amines • Aromatic amines • Polyamines • Indoles • Phenols • Carbonhyrate derivatives

27. Middle molecules as uremic toxins The middle molecule hypothesis: • Peritoneal membrane was more leaky and thus more effective at removing middle molecules than the hemodialysis membranes. • It is well established that CAPD patients may survive and thrive as well as HD patients do, even though their average weekly clearance of urea is considerably lower than that for HD patients.

28. Determination and characterization of MMs • Many methods were applied to isolate or separate MMs from plasma, serum, dialysate, ultrafiltrate, and urine: gel permeation chromatography, ion exchange chromography, electrohporetic method, paper or thin layer chromography • MM fractions contains peptides or conjugated amino acids but only some of them have been isolated in pure form and their molecular strctured idertified • Carbohydrate with neurotoxic property was also identified

29. Toxic effects of crude MM fractions • Inhibition of proliferation of undifferentiated cell lines and hematopoietic cell lines, depression of several immmune function, increase hemolysis, cardiotoxicity, inhibition of platelet aggregation, inhibition of glucose utilization, inhibit protein synthesis and amino acid transport, inhibition of mitochondrial respiration • Inhibit osteoclast mitogenesis • Some enzyme activities are also inhibited

30. Clinical studies of MMs • “sick” uremic patients tend to have higher MMs in plasma than patients free of complications • Some studies support MMs involve in uremic neurotoxicity • Correlation have been found between plasma levels of immunoreactive parathyroid hormone and MMs • Patients on CAPD have been shown to have lower plasma MM levels than patients on intermittent hemodialysis • There is strong indirect evidence that compounds in the MM weight range, which accumulate in uremia, are toxic. Most of these compounds are still not fully identified, their role as uremic toxins remains unidentified.

31. The trade-off hypothesis • Certain humoral factors may exert toxic effects accumulate in uremia, not as a consequence of reduced renal excretion but due to homeostatic adaption to the reduced glomerular filtration rate • Natriuretic factors, parathyroid hormone

32. Natriuretic factors • Stimulate by volume expansion • Accounts for decreased fractional absorption of sodium in chronic uremia when the glomerular filtration falls • Elavated plasma concentrations showed digoxinlike activity and inhibit Na-K-ATPase

33. Parathyroid hormone • Incresed in uremic patients as consequence of phosphate retention, decreasing ionized calcium stimulate parathyroid glands to increase PTH secretion • PTH hypersecretiopn in uremic patients : encephalopathy, neuropathy, dementia, bone disease, soft tissue calcification, hypertension, cardiomegaly, carbohydrate intolerance, anemia, sextual dysfunction

34. High-molecular-weight peptides and proteins • Ribonuclease • Granulocyte-inhiting proteins • Complement factors • Beta2-Microglobulin and Dialysis-related amyloidosis