1. NON-TRADITIONAL RENAL REPLACEMENT THERAPY Hafez Bazaraa

2. NON-TRADITIONAL RENAL REPLACEMENT THERAPY What? Why? How?

3. RENAL FUNCTIONS Excretion of non-volatile wastes Water, electrolyte, acid-base balance Hormonal regulatory functions (EPO, Vit D,..)

4. RENAL FAILURE Excretion of non-volatile wastes Water, electrolyte, acid-base balance Hormonal regulatory functions (EPO, Vit D,..)

5. RENAL FAILURE  RRT TRANSPLANTATIONDIALYSIS

6. RENAL FAILURE  RRT TRANSPLANTATIONDIALYSIS HDPD Deceased donor Living donor (Rel., Unrel.)

7. RRT facts The kidney was the first solid organ whose function was approximated by a synthetic device. RRT with hemodialysis or CPD has been the only successful long term ex vivo organ substitution therapy to date. The kidney was the first organ to be successfully transplanted.

8. Dialysis? Kolff, a Dutch physician constructed the first working dialyzer in 1943 during the Nazi occupation of the Netherlands Using sausage casings, beverage cans, a washing machine, and other items 16 patients with ARF unsuccessfully treated In 1945, a 67-year-old comatose woman regained consciousness following 11 hours of HD and lived 7 yrs before dying from an unrelated condition.

9. Transplantation? 1906from sheep, pigs, goats and primates without anti-rejection drugs. 1936First human-to-human kidney transplant from a deceased donor with a different blood type. 1954First successful kidney transplant (identical twins) 1966 First successful pediatric kidney transplantation

10. How traditional? Transplantation Modern VA Biocompatible dialyzer membranes Bicarbonate dialysis UF & Na profiling EPO, Active vit D CPD, CCPD Historical innovations NOW TRADITIONAL

11. RRT: how traditional is non-traditional?

12. Historical innovations Established non-traditional RRT Experimental/ future RRT & challenges

13. NON-TRADITIONAL RENAL REPLACEMENT THERAPY What? Why? How? Partial RRT Survival vs quality of survival Risks of treatment Organ shortage

14. NON-TRADITIONAL RENAL REPLACEMENT THERAPY What? Why? How? Partial RRT -Dx replaces mostly filtration -Not all functions -Intermittent nature Survival vs quality of survival - Inadequate long-term outcomes -Dependency -Quality of life Risks of treatment - Infections -Medication SE -VA complications -Pain, discomfort Organ shortage If you (logically) think Tx is the best option

15. NON-TRADITIONAL RENAL REPLACEMENT THERAPY What? Why? How? Partial RRT Survival vs quality of survival Risks of treatment Organ shortage

16. NON-TRADITIONAL RENAL REPLACEMENT THERAPY Transplantation modifications Dialysis modifications Intestinal dialysis Regenerative medicine The two-step dialysis concept Hybrids Whole-organ engineering WARNING Strange Ideas Ahead

17. Transplantation practice Novel immunosuppression protocols Working with the immune system Cell therapies (MSCs, Treg, etc)

18. Creatinine 113 D Urea 60 D Glucose 180 D Vit. B 12 1,355 D  2-M 11,800 D Albumin 66,000 D IgG 150,000 D Dialysis Membrane Flux and Selectivity

19. CRRT Physiological (slow, continuous) Physiological (filtration-replacement) Well controlled therapy Complex, expensive therapy

20. Back to nature 100 L/m2/d Plasma - proteins

21. Ultrafiltration Replacement (substitution) Net UF (fluid removal) HEMOFILTRATION

22. Solute transport: diffusion

23. Solute removal: convection (solvent drag)

24. Clearance: Convection vs. Diffusion

25. Hemofiltration membrane permeability phosphate bicarbonate ionized Ca++ interleukin-6 endotoxin vancomycin heparin pesticides ammonia   albumin  protein-bound medications  platelets Water Electrolytes Non-protein-bound Drugs Toxins Cytokines

26. Long-term oHDF

27. HD machine prepares substitute from ultrapure dialyzate (part of the benefit)

28. Long-term oHDF B2 microglobulin amyloidosis EPO resistance MBD & hyperPTH Chronic infl. state CV outcome

29. Daily nocturnal HD Again more physiological Fluid management advantages VA complications/loss ++ Dependency ++

31. home dialysis Home dialysis

32. (trans) portable HD systems Home dialysis

33. 30-Kg dialysis machine PureFlow SL System: Compact water ttt + conc bags Nx Stage System One 2005 Systems using sorbents to regenerate dialysate (Fresenius; pending FDA approval)

34. Intestinal dialysis imp

35. Intestinal dialysis ESRD; GFR<5, not oligo-anuric 7 L dialyzate-mannitol over 3 hrs 11-22% dec in urea, not creat 2-3x/wk  uremic symptoms improved with slight prolongation of life.

36. Intestinal dialysis (non-dialytic urea “N” lowering therapy) Ingesting Acacia and certain probiotics With a low protien diet Stimulate the growth of intestinal flora Increases the transfer of waste nitrogen from the surrounding blood stream into the intestine

37. Intestinal dialysis We have used GIT for Removal of K Removal of N Addition of Ca, HCO 3 Removal of fluid

38. NON-TRADITIONAL RENAL REPLACEMENT THERAPY Transplantation modifications Dialysis modifications Intestinal dialysis Regenerative medicine The two-step dialysis concept Hybrids Whole-organ engineering

39. Regenerative medicine replacing, engineering or regenerating human cells, tissues or organs to restore or establish normal function injection of stem cells (cell therapies) induction of regeneration by biologically active molecules (administered or secretion by infused cells) transplantation of in vitro grown organs and tissues (tissue engineering).

40. MSCs in experimental evidence

41. Ameliorate injury and contribute to repair Immunomodulatory effects Acute tubular injury CKD Desensitization Early IFTA

42. Back to dialysis FILTRATION FUNCTION High volume effluent SUPPLEMENTED WITH High volume dialyzate for diffusion High volume substitute for convection

43. The TWO-STEP dialysis concept FILTRATION FUNCTION High volume effluent SUPPLEMENTED WITH Effluent purification & reuse Effluent reabsorption & reinfusion

44. Wearable HD solutions Sorbent nano High flux miniature dialysis circuit Dialyzate continuously purified with nanostructured sorbents Catalytic oxidation of urea & creatinine

45. Wearable HD solutions Home dialysis CCl 30 L/d; 20 mL/min (assuming creat 6mg/dL)

46. 150 mL dialyzate 150 g sorbents With filters, sensors, pumps & battery  2-Kg system

47. Wearable HD solutions Home dialysis Wearable HD solutions

48. Home dialysis

49. Prototype for animal trials

50. Automated Wearable Art. Kid.

51. The TWO-STEP dialysis concept FILTRATION FUNCTION High volume effluent SUPPLEMENTED WITH Effluent purification & reuse Effluent reabsorption & reinfusion

52. Bioartificial dialyzers Animal renal cortex used to extract tubular progenitor cells Expanded in culture Seeded in protein polymer coated hollow fibres Culture medium perfused extra then intra fiber & replaced CONFLUENT CELL GROWTH IN 14 DAYS The Artificial Kidney: Physiological Modeling and Tissue Engineering, edited by John K. Leypoldt. ©1999 R.G. Landes

53. Single hollow fiber BIOARTIFICIAL TUBULE 99% inulin recovery Active transport Fluid reabsorption Vit D activation 97 cm2-0.7 m2 multiple hollow fiber RENAL ASSIST DEVICE

54. Hemofilter-RAD in series

55. RENAL FAILURE  RRT TRANSPLANTATIONDIALYSIS A hybrid therapy

56. iRAD implantable renal assist device nano filter (Si) with live kidney cells

58. NON-TRADITIONAL RENAL REPLACEMENT THERAPY Transplantation modifications Dialysis modifications Intestinal dialysis Regenerative medicine The two-step dialysis concept Hybrids Whole-organ engineering

59. Bioengineering Perfused bioscaffold

61. Bioengineering 3D printing

65. There is no guarantee that a new idea will effect a real change There is a guarantee that without a new idea, nothing would change

67. Thank you