Uremic Toxins Overview


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Review (ca 2007) of Uremic Toxins Accumulating in Patients with Chronic and End Stage Renal Disease modified from a presentation I gave in Fellow's Grand rounds.

Relied heavily on publications from the EU Toxin Work Group Work, which provides more up to date information:


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Uremic Toxins Overview

  1. 1. Uremic Toxins Christos Argyropoulos Renal Grand Rounds 15/10/2007
  2. 2. General Outline <ul><li>Definitions of terms </li></ul><ul><li>Conceptual Pathogenetic Model of Uremia and the “Residual Syndrome” </li></ul><ul><li>Experimental Evidence for the Model </li></ul><ul><li>What can we do? </li></ul>
  3. 3. The “Chosen” Ones <ul><li>Review selected compounds from the uremic hall of fame </li></ul><ul><li>Impossible to review everything, since the literature is extensive (includes both gels and small p – values!) </li></ul><ul><li>Focus on less well known culprits (no PTH, CaxP, beta2 microglobulin, K, Phos today) </li></ul><ul><li>Focus on the ones that should make us rethink RRTs </li></ul>
  4. 4. Uremia <ul><li>A construct of the 19 th century </li></ul><ul><li>Literal meaning “Urine in the blood” </li></ul><ul><li>Denotes symptoms and signs in patients with “failing” kidneys irrespective of the initiating cause of renal failure </li></ul><ul><li>Underlying conceptual pathogenetic model: intoxication by accumulation </li></ul>
  5. 5. Uremia <ul><li>Manifestations of the uremic syndrome: </li></ul><ul><li>Nausea, vomiting, loss of appetite, wt loss, abnormalities of coagulation cascade, GI bleeding, pruritus , serositis, volume overload, hypertension, soft tissue calcification, pulmonary edema, confusion, lethargy, death </li></ul>
  6. 6. Of theories, measurements and experiments <ul><li>All phenomena have a cause (even if it cannot exceed the p-value of 0.05) </li></ul><ul><li>One cannot measure what does not exist </li></ul><ul><li>One cannot know what one cannot measure </li></ul><ul><li>One versus multiple toxins (the rise and fall of urea) </li></ul><ul><li>The higher the concentration (signal), the easier to measure and study </li></ul><ul><li>Counting missing limbs is easier than MALDI-TOF/MS/2D-protein electrophoresis </li></ul>
  7. 7. The “Residual” Syndrome <ul><li>Introduction of dialytic therapies provided experimental evidence for the validity of the intoxication model of uremia: </li></ul><ul><ul><li>Visual Evidence: uremic frost disappeared </li></ul></ul><ul><ul><li>Comatose patients were waking up </li></ul></ul><ul><ul><li>Survival was increased </li></ul></ul><ul><li>What we see today is a different life-threatening condition that is known as the “residual uremic syndrome” </li></ul><ul><li>Academically, it has been a rewarding syndrome that has generated publications with multiple , highly significant p-values about itching, depressed, dying, elderly dialysis patients </li></ul>
  8. 8. Clinical Manifestations of the “Residual” Syndrome <ul><li>S ubtle signs of malnutrition </li></ul><ul><li>I ncreased susceptibility to infection </li></ul><ul><li>Increased susceptibility to cardiovascular complications </li></ul><ul><li>L ow-grade serositis </li></ul><ul><li>I mpaired vascular reactivity </li></ul><ul><li>H ypothermia </li></ul><ul><li>Reduced exercise capacity and O2 utilization </li></ul><ul><li>Fatigue </li></ul><ul><li>S ubtle psychological disturbances such as loss of focus and ambition (or is it depression?) </li></ul><ul><li>Sleep disturbances </li></ul><ul><li>Restless Legs </li></ul>
  9. 9. Possible Causes of the “Residual” Syndrome <ul><li>Accumulation of: </li></ul><ul><ul><li>large molecular weight solutes that are difficult to remove by dialysis </li></ul></ul><ul><ul><li>protein-bound small molecular weight solutes that are difficult to remove by dialysis </li></ul></ul><ul><ul><li>dialyzable solutes that are incompletely removed </li></ul></ul><ul><li>Indirect phenomena : </li></ul><ul><ul><li>Accelerated protein “aging” </li></ul></ul><ul><ul><li>Inflammation </li></ul></ul><ul><ul><li>T issue calcification </li></ul></ul><ul><ul><li>T oxic effect of hormone imbalance </li></ul></ul><ul><li>A toxic effect of the dialysis itself </li></ul>Semin. Dial. (2001) 14(4):246-251
  10. 10. Possible Causes of the “Residual” Syndrome <ul><li>A. Intoxication By Accumulation </li></ul>
  11. 11. Uremic Solutes (The NEMJ view) N Engl J Med 357:1316, September 27, 2007
  12. 12. A Systematic Approach To Uremic Retention Solutes <ul><li>EUTox: workgroup of the ESAO formed in 1999 to </li></ul><ul><li>systematically categorize, </li></ul><ul><li>experimentally study uremic retention molecules ( general aim ) </li></ul><ul><li>More specifically detect the “renal failure specific” factors which underlie vascular damage (genome, proteome, secretome) </li></ul><ul><li>design, develop and improve extracorporeal treatment systems (industrial partners) </li></ul><ul><li>Apply such knowledge to bioartificial reactors and regenerative medicine applications (industrial partners) </li></ul>http://www.uremic-toxins.org/
  13. 13. A Systematic Approach To Uremic Retention Solutes <ul><li>A database of 857 publications between 1966 and 2002 abstracted from Medline </li></ul><ul><li>Database concerns solutes, and inter-individual variability of concentrations </li></ul><ul><li>Manual classification in three categories: </li></ul><ul><ul><li>Small solutes with no protein binding </li></ul></ul><ul><ul><li>Middle Molecules (>500Da) </li></ul></ul><ul><ul><li>Protein Bound Molecules </li></ul></ul><ul><li>Classification scheme emphasizes characteristics that influence removal by extracorporeal therapy modalities </li></ul>KI, 63 (2003) 1934-1943
  14. 14. A Systematic Approach To Uremic Retention Solutes http://www.nephro-leipzig.de/eutoxdb/index.php
  15. 15. A Systematic Approach To Uremic Retention Solutes http://www.nephro-leipzig.de/eutoxdb/index.php
  16. 16. A Systematic Approach To Uremic Retention Solutes <ul><li>Compounds that accumulate the most are the ones which are a) protein bound b) of size that exceeds the cutoff of our dialysis membranes </li></ul><ul><li>Critical limitation: one cannot know what one cannot measure </li></ul>KI, 63 (2003) 1934-1943
  17. 17. A Systematic Approach To Uremic Retention Solutes <ul><li>For people who like p-values, the KI paper has many, small values to explore </li></ul><ul><li>For people who like to think abstractly a few disturbing features emerge: </li></ul><ul><ul><li>The non-toxic “stuff” we measure (SCr/Urea) increases far less than the toxic “stuff” we do not routinely measure </li></ul></ul><ul><ul><li>There is wide inter-individual variability in the retention factors of different solutes </li></ul></ul><ul><ul><li>Conventional renal replacement therapies cannot remove many biologically significant retention solutes </li></ul></ul>KI, 63 (2003) 1934-1943
  18. 18. Causes and Consequences of Variability <ul><li>Differences in laboratory techniques (e.g. p-cresol concentration by GCMS is x6 c.t HPLC) </li></ul><ul><li>Structural modification of molecules </li></ul><ul><li>True inter-individual, ethic and geographic differences in the rate of generation of compounds </li></ul><ul><li>Differences in dialysis modalities </li></ul><ul><li>Wide range of biological effects possible (may account for differences in the epidemiology of complications of CKD/ESRD) </li></ul>Nephrology Dialysis Transplantation July 15 2007 , doi:10.1093/ndt/gfm151
  19. 19. Clinical Implications of Solute Accumulation <ul><li>Honestly we do not really know (notable exception: b2 microglobulin) </li></ul><ul><li>However they must do something (or else the patients are “faking” both the uremic residual syndrome and the improvement noted after transplantation) </li></ul><ul><li>Evidence for the accumulation and biological toxicity of individual compounds is indirect and difficult to obtain (but it can be done at least in vitro) </li></ul>
  20. 20. Clinical Implications of Solute Accumulation <ul><li>Source of uremic solutes (protein breakdown, environment, dialytic modalities, GIT bacteria) </li></ul><ul><li>Concomitantly prescribed drugs that interfere with the free fraction of uremic solutes </li></ul><ul><li>Residual renal function </li></ul><ul><li>Differences in dialysis dose and membrane flux </li></ul><ul><li>Multi-compartmental kinetics and differential cellular accumulation e.g. differences in organic transporter activity </li></ul>
  21. 21. Urea <ul><li>Probably minimal if any toxicity. </li></ul><ul><li>Clinical correlates: ICU consults! </li></ul><ul><li>In vitro studies: inhibition of volume sensitive transporters, decreased 2,3 DPG binding to hemoglobin, inhibition of NaK2Cl RBC transporter, macrophage iNOS (at unrealistically high concentrations) </li></ul>
  22. 22. Guanidines <ul><li>Large group of metabolites of arginine </li></ul><ul><li>Variable Mechanisms of toxicity. </li></ul><ul><li>Water soluble </li></ul><ul><li>Differential distribution in cellular compartments </li></ul>
  23. 23. Guanidines - Creatinine <ul><li>Large group of metabolites of arginine </li></ul><ul><li>Variable Mechanisms of toxicity. </li></ul><ul><li>The most innocuous one is Creatinine (has been associated with ICU consults) </li></ul><ul><li>In vitro studies: inhibition of chloride transport activity, reduces contractility of SMCs (at 5 times the concentrations seen in typical cases of uremic coma) </li></ul>
  24. 24. Guanidines – Non Creatinine <ul><li>Group of water soluble molecules: Guanidine (G), Guanidinosuccinate (GSA), Methylguanine (MG), Asymmetric Dimethyarginine (ADMA), Guanidino-propionic acid (GPA) and many others </li></ul><ul><li>Neurotoxins - seizures (GPA, MG) through competitive inhibition of GABA/Gly and agonistic effects on NMDA (Glutamate) receptors </li></ul><ul><li>Inferred role in memory disturbances of dialysis patients through interference with Glutamate neurotransmission </li></ul>
  25. 25. Memory, Emotions, Seizures: Kidney v.s. Brain <ul><li>Associate memory formation in the mammalian CNS is grounded on the synaptic circuitry of hippocampal area CA1 </li></ul><ul><li>Experiments in animals, and fMRI imaging strongly suggest that limbic structures are involved in the pathogenesis and progression of depression </li></ul><ul><li>The same area of the brain is involved in significant proportion of complex partial seizures (target in surgical Tx for Epilepsy) </li></ul>
  26. 26. Memory, Emotions, Seizures: Kidney v.s. Brain <ul><li>Depression in non-uremic individuals is associated with reductions in the volume of the hippocampal/amygdala complex </li></ul><ul><li>Such reductions correlate with disease severity and duration </li></ul>Neuropsychopharmacology (2004) 29, 952–959
  27. 27. Memory, Emotions, Seizures: Kidney v.s. Brain <ul><li>The effects of GSA administration was recently examined in rats </li></ul><ul><li>The study demonstrated dose dependent effects on: </li></ul><ul><ul><li>reductions of hippocampal volume, </li></ul></ul><ul><ul><li>impaired performance in cognitive tasks (passive avoidance, water maze test), </li></ul></ul><ul><ul><li>Impaired psychomotor performance (open exploration, spontaneous activity, social exploration) </li></ul></ul>Physiology and Behaviour 84(2) , 15 February 2005, Pages 251-264
  28. 28. Memory, Emotions, Seizures: Kidney v.s. Hippocampus http://en.wikipedia.org/wiki/Morris_water_maze Physiology and Behaviour 84(2) , 15 February 2005, Pages 251-264
  29. 29. Memory, Emotions, Seizures: Kidney v.s. Hippocampus <ul><li>Associative, declarative memory formation requires simultaneous activation of pre and post-synaptic neurons in the hippocampus </li></ul>http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.TOC&depth=2
  30. 30. Memory, Emotions, Seizures: Kidney v.s. Hippocampus KI (2001) 59(S78): 77-83 GSA competes for the Mg2+ binding site of the NMDA channel leading to over-activation of the channel, Ca2+ influx, neurotoxicity and cell death
  31. 31. Guanidines – Other Effects <ul><li>Immunosuppressive properties: inhibition of PMN SOD (GPA, GSA), suppression of NK response to IL-2 </li></ul><ul><li>Increased activation induced apoptosis of lymphocytes </li></ul><ul><li>Inhibition of iNOS production (ADMA) leading to vasoconstriction and HTN </li></ul><ul><li>Structural modification of other proteins (esp albumin) and subsequent release of Homocysteine) </li></ul>
  32. 32. P-Cresol and Conjugates <ul><li>Phenolic acid derivative, produced by intestinal bacteria as a result of the metabolism of Tyr and Phe </li></ul><ul><li>Other sources: psychedelic drugs, smoking </li></ul><ul><li>Clinical Effects: </li></ul><ul><ul><li>Hepato-toxin, </li></ul></ul><ul><ul><li>inhibits free O2 generation inside PMNs, </li></ul></ul><ul><ul><li>Inhibits expression of adhesion molecules for monocytes and PMNs in uremic animals, </li></ul></ul><ul><ul><li>Protein bound (>98%) in conjugated form </li></ul></ul><ul><ul><li>Inefficiently removed by HD, but not by PD </li></ul></ul><ul><li>Oral absorbents (AT120) decrease levels in experimental models and attenuate progression of glomerulosclerosis in the 5/6 rat model </li></ul>
  33. 33. 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid <ul><li>Urofuranic acid derivative </li></ul><ul><li>Strongly lipophilic and protein bound </li></ul><ul><li>Major competitive inhibitor of drug binding, hepatic SAM </li></ul><ul><li>Interferes with conversion of T4 to T3 </li></ul><ul><li>Interferes with oxidation of NADH compounds in mitochondria </li></ul><ul><li>Levels minimally affected by either low flux or high flux dialysis </li></ul>
  34. 34. Homocysteine (Hcy) <ul><li>Sulfur containing aa produced by demethylation of Met </li></ul><ul><li>Elevations of Hcy lead to cellular accumulation of S-adenosyl-Hcy which competes with SAM (a co factor for transmethylation reactions) </li></ul><ul><li>Widespread hypo-methylation (a key epigenetic transcriptional control mechanism) ensues </li></ul><ul><li>Anatomically this leads to accelerated atherosclerosis in rat models and in vitro proliferation of VSMCs </li></ul><ul><li>In the general population, an increase in Hcy concentration is associated with CV mortality </li></ul><ul><li>Note that in both meta-analysis and randomized trials analyzed by ITT, exogenous folate administration did not attenuate CV mortality </li></ul><ul><li>Genetic and epidemiologic studies analyzed by AT disagree </li></ul>JAMA. 2006;296:2720-2726 http://www.medscape.com/viewarticle/548317
  35. 35. Homocysteine (Hcy) <ul><li>Levels are increased x2-4 in ESRD </li></ul><ul><li>Mechanism of elevation is unclear ( impairment of Hcy transsulphuration and remethylation ) </li></ul><ul><li>Exogenous folate administration may improve metabolic flux in the C1 pathways without modifying Hcy levels </li></ul><ul><li>One study in ESRD patients showed no clinical benefit as far as CV outcomes are concerned ( J Am Soc Nephrol 2004; 15: 420–426 ) </li></ul><ul><li>HOST study will be completed at the end of this year </li></ul>Nephrology Dialysis Transplantation 2006 21(5):1161-1166
  36. 36. Small molecular toxins and the dose of dialysis <ul><li>Theoretical considerations argue that these compounds should cross the membrane at the same efficiency as Urea </li></ul><ul><li>Even though this is true, total body clearance is vastly different: a RR of 77% for urea amounts to a RR of 49% for GSA and 55% for MG </li></ul><ul><li>URR may be used to estimate the dialyzer extraction ratio (will be the same for all “similar” compounds) ≠ RR </li></ul><ul><li>The degree of accumulation requires knowledge of the degree of generation (which is not the nPCR!) and the order of the corresponding compartmental model </li></ul><ul><li>Dose measurement schemes will have to be reconsidered and validated for known toxins (e.g. is (KT/V) GSA linearly related to (KT/V) UREA ? </li></ul>Am J Kidney Dis. 2007 Aug;50(2):279-88.
  37. 37. Possible Causes of the “Residual” Syndrome <ul><li>B. Indirect Effects and the inflammatory loop model of uremia </li></ul>
  38. 38. Beyond small molecules <ul><li>Traditional view of pathophysiology of uremic complication : retention of solutes (small molecules) </li></ul><ul><li>Efficacy of PD attributed to clearance of “middle molecules” of MW between 300Da-12kDA </li></ul><ul><li>Prototypical middle molecule: B2-MG (?PTH) </li></ul><ul><li>The existence of other “middle” molecules could not be demonstrated until the introduction of proteomic techniques (“one cannot know what one cannot measure”) </li></ul>
  39. 39. Proteomics and the Quest for Middle Molecules <ul><li>Proteome: “ the entire complement of proteins expressed by a genome, cell, tissue or organism “ </li></ul><ul><li>Proteomics: The study of the proteome with biochemical techniques (2D electrophoresis, CE coupled with ESI-TOF MS </li></ul><ul><li>Generates an “unbiased” fingerprint of what lies across the twilight zone (the dialysate side!) </li></ul><ul><li>Middle molecules can now be “spotted” </li></ul>
  40. 40. Proteomics and the Quest for Middle Molecules Nephrology Dialysis Transplantation 2004 19(12):3068-3077; doi:10.1093/ndt/gfh509 http://www.decodon.com/
  41. 41. Effect of Membrane Flux in Maintenance Hemodialysis Nephrology Dialysis Transplantation 2004 19(12):3068-3077; doi:10.1093/ndt/gfh509
  42. 42. Effect of Membrane Flux in Maintenance Hemodialysis <ul><li>In UF from uremic plasma 1394 pps were identified in high flux membranes v.s. 1046 (low flux) </li></ul><ul><li>Normal plasma contained 544 and 490 respectively </li></ul><ul><li>Post HF dialysis plasma showed the same distribution of pps as normal plasma </li></ul><ul><li>Mass distribution differed between HF and LF membranes </li></ul><ul><li>“ Low flux” membrane used in that study (F10) has a cutoff of 5200 Da </li></ul>Nephrology Dialysis Transplantation 2004 19(12):3068-3077; doi:10.1093/ndt/gfh509
  43. 43. Clinical Application of Proteomics : Defining the Problem <ul><li>This one had multiple interesting and statistically significant p-values </li></ul><ul><li>Significant predictors of itchiness were: nationality (Italians topped the list with 55%), duration of ESRD (>3 mo), male sex </li></ul><ul><li>Itchiness was a predictor of mortality (author hypothesized a relation with sleep disturbances) and so was depression </li></ul>
  44. 44. Clinical Application of Proteomics : Proposing an Intervention <ul><li>This one also had multiple interesting and statistically significant p-values </li></ul><ul><li>The self-assessed VAS itching strength scores decreased by 15% after 1 month, 30% after 2 months, and 55% after 6 months, and itching duration decreased by, respectively, 10, 22 and 44% at the same time; 2 months after the end of the study, both scores had slightly increased, but ß2-microglobulin levels significantly decreased ( P < 0.03); </li></ul>Nephrology Dialysis Transplantation 2007 22(Supplement 5):v8-v12; doi:10.1093 /ndt/gfm293
  45. 45. Clinical Application of Proteomics : Why does the intervention work? <ul><li>This one also had multiple interesting trivia </li></ul><ul><li>PMMA membranes are “protein-leaking” and protein adsorbing and have been used succesfully in the Tx of uremic pruritus for the last 10 years </li></ul><ul><li>After eluting the adsorbed protein components, patients with itching showed a band in the 160KDa region that was not an IgG molecule </li></ul>Nephrology Dialysis Transplantation 2007 22(Supplement 5):v13-v19; doi:10.1093/ndt/gfm295
  46. 46. Clinical Application of Proteomics : Why does the intervention work? Nephrology Dialysis Transplantation 2007 22(Supplement 5):v13-v19; doi:10.1093/ndt/gfm295
  47. 47. Clinical Application of Proteomic Research: PD <ul><li>A study in 44 PD patients with different transport characteristics </li></ul><ul><li>Screened for differences in protein excretion with 2D-PAGE followed by identification with MALDI-TOF </li></ul><ul><li>Previous episodes (>1mo) of tx peritonitis associated with ↑↑ free light chains in the PD fluid </li></ul><ul><li>High transporters were “leaking” Apo-AI a component of HDL </li></ul><ul><li>Report that the proteome profiles are similar to the ones obtained from normal urine (unfortunately the data were not shown) </li></ul>J. Proteome Res., ASAP Article 10.1021/ pr0702969 S1535-3893(07)00296-5
  48. 48. Low – Molecular Weight Proteins that accumulate in ESRD J Am Soc Nephrol 13:S41-S47, 2002
  49. 49. Accumulation of solutes v.s. Cumulative Protein Damage <ul><li>So called middle molecules consist of both retention molecules and modified versions of proteins whose total concentration may remain in the normal range </li></ul><ul><li>Such protein damage may provide the missing link between retention and inflammation/malnutrition </li></ul>
  50. 50. Accumulation of solutes v.s. Cumulative Protein Damage <ul><li>Initiating Events: oxidative stress of CKD/ESRD/carbonyl stress (from abnormal lipid and sugar metabolism) </li></ul><ul><li>Intermediate molecular changes: hydroxylation, nitration and chlorination of aromatic aa,sulfoxidation of Met in proteins </li></ul><ul><li>End result: deranged protein metabolism and functional alterations </li></ul>
  51. 51. Major Classes of Irreversible Protein Damage Products <ul><li>Advanced Oxidation End Products (AOPP) : d/t modification of Tyr residues </li></ul><ul><li>Advanced Lipoxidation End Products (ALE): d/t Michael reaction of α , β -unsaturated aldehydes to the NH2 group of Lys, imidazolone group of His and the sulphydryl group of Cys </li></ul><ul><li>Advanced Glyc(oxidation) End Products : predominantly non- fluorescent glyoxal derivatives of Lys rather than the “traditional” fluorescent varieties found in DM. </li></ul><ul><li>Tissue fluorescent AGEs: measure of cumulative exposure to pro-inflammatory and oxidative stress. Skin autofluorescence is a predictor of mortality in ESRD patients </li></ul>Nephrology Dialysis Transplantation 2007 22(Supplement 5):v20-v36; doi:10.1093/ndt/gfm294 J Am Soc Nephrol 16: 3687-3693, 2005
  52. 52. Tissue AGEs and mortality in ESRD
  53. 53. Putting it all together <ul><li>A multi-step “inflammatory loop” model for the pathogenesis of uremia was proposed recently </li></ul><ul><ul><li>Carbonyl+Oxidation Stress lead to protein damage </li></ul></ul><ul><ul><li>Protein End products are recognized by the RAGE superfamily of membrane receptors </li></ul></ul><ul><ul><li>Initiation of inflammatory cascade </li></ul></ul><ul><ul><li>Generation of reactive oxygen and nitrogen species </li></ul></ul><ul><ul><li>Further protein damage leading to more inflammation and production of reactive radicals (positive loop) </li></ul></ul><ul><ul><li>An important independent source of both AGE and inflammatory mediators may be dialysis itself (PD and HD respectively) </li></ul></ul><ul><ul><li>The loop will be broken by increases in the GFR </li></ul></ul>Nephrology Dialysis Transplantation 2007 22(Supplement 5):v20-v36
  54. 54. Putting it all together Nephrology Dialysis Transplantation 2007 22(Supplement 5):v20-v36
  55. 55. Putting it all together Nephrology Dialysis Transplantation 2007 22(Supplement 5):v20-v36
  56. 56. Knowing is not enough, we must apply.   Willing is not enough, we must do. Goethe
  57. 57. What do we know? <ul><li>Not much, but certainly we have ended the beginning of the quest for knowledge </li></ul><ul><li>The pathogenesis of the uremic residual syndrome has evolved from the accumulated toxicity model of the 19 th century </li></ul><ul><li>Both accumulation of “stuff” and cumulative damage from “stuff” are to blame </li></ul><ul><li>Accumulation is they key word … we’ve got to give more “GFR” back </li></ul>
  58. 58. What can we do? <ul><li>The best way of giving GFR back is a transplant </li></ul><ul><li>If the organ shortage could be solved, then the precise nature of the uremic toxins can be left unexplored </li></ul><ul><li>It is unlikely that we can achieve this goal any time soon for all our patients so we’ve got to improve our dialysis Tx </li></ul>
  59. 59. What can we do? <ul><li>The (unsatisfactory) answer is that we have got to give more “machine GFR” back </li></ul><ul><li>One cannot know (that one gives more GFR) what one cannot measure (dose of dialysis) </li></ul><ul><li>However kinetic models of the dose of dialysis based on (KT/V) urea have to be abandoned or drastically modified </li></ul><ul><li>Possible solution: analysis of large cohorts of people who do well and people who do not do well with detailed kinetic model and validation of population PK/PD models (we did that with FK/CSA!) </li></ul>
  60. 60. What can we do? <ul><li>In light of the inadequacy of our current kinetic constructs, we should re-examine the major dialysis trials (they assume the kinetic constructs are correct) because more dialysis (and higher flux) may in fact be better </li></ul><ul><li>Itching, depressed, fatigued dying elderly dialysis patients may help us “spot” the correct dialysis dosing schedules (ASK for symptoms, study what goes down the drain and what stays behind) </li></ul><ul><li>Follow up with more efficient dialysis along or even instead of SSRIs and moisturizing lotions) </li></ul>
  61. 61. What can we do? <ul><li>The molecular analysis of what goes down the drain points out that no matter how much (KT/V) UREA/GSA/etc we give there will be bigger bad guys that stay behind </li></ul><ul><li>Ideas to test in RCTs (should not be analyzed by the ITT): </li></ul><ul><ul><li>Hemo-diafiltration (adds convective clearance) </li></ul></ul><ul><ul><li>Protein Leaking/Absorbent Membranes (removes larger “stuff”) </li></ul></ul><ul><ul><li>More frequent dialysis (improves small moleculer clearance, BP and volume control) </li></ul></ul><ul><ul><li>Biocompatible membranes and solutions (reduces inflammation from the machine/PD solution) </li></ul></ul>
  62. 62. If you are interested to find out more … <ul><li>EuTOX database: </li></ul><ul><ul><li>http://www.uremic-toxins.org/ </li></ul></ul><ul><li>Lowrie EG. The kinetic behaviors of urea and other marker molecules during hemodialysis. Am J Kidney Dis. 2007 Aug;50(2):181-3 </li></ul><ul><li>Galli F. Protein Damage and inflammation in uraemia and dialysis patients Nephrology Dialysis Transplantation, 2007 22 Supplement 5 20-36 (Special Issue on uremic toxins) </li></ul><ul><li>Weissinger et al Proteomics: a novel tool to unravel the pathophysiology of uremia. Nephrology Dialysis Transplantation ( 2004 ) 19: 2068-3077 </li></ul><ul><li>Depner T.A. Uremic Toxicity: Urea and Beyond. Seminars in Dialysis (2001),14(4): 246-251 </li></ul><ul><li>Locatelli F. et al. A critical assessment of Uremia Research Blood Purif 2006,24:71-78 </li></ul><ul><li>Vanholder R et al. What is uremia? Retention versus Oxidation Blood Purif 2006,24:33-38 </li></ul>