roadmap towards future renal replacement therapy and the
TRANSCRIPT
Dept. Nephrology
Roadmap towards future renal replacement therapy and the concept of an artificial kidney
Branko Braam, MD PhDInternist/nephrologist, Eur. Hypertension SpecialistDepartment of Nephrology and Hypertension, Univ. Med. Center, Utrecht, The [email protected]
Dept. Nephrology
‘We just haven’t been flapping them hard enough’
Do we have a dream?
Dept. Nephrology
Do we have a dream?
Four innovative potential solutions can be identified for replacement of renal function when the kidneys fail:
(1) a technical device, which is small and implantable and perhaps uses functionality of human cells;
(2) restoration of the kidney by refurbishing the damaged kidney with new cells, making use of stem cells and of knowledge on programming;
(3) to (partially) grow a kidney in vitro, using therapeutic cloning;
(4) to use different organs and tissues to replace different functions of the kidney.
Dept. Nephrology
Do we have a dream?
Function Approach Limitation(s)
Control of ECFV Ultrafiltration during hemodialysis Intermittent volume overload
Rapid removal of volume associated with hypotension
Adequate control of ECFV hard to precisely assess
Peritoneal dialysis Problems directly associated with PD technique (peritoneal
infections, catheter dislocation, ultrafiltration failure)
Removal of uremic toxins Hemodialysis Large variety in effectiveness of clearance of different
uremic toxins
Hemodiafiltration Large variety in effectiveness of clearance of different
uremic toxins, however, possibly somewhat more effective
Peritoneal dialysis Large variety in effectiveness of clearance of different
uremic toxins
Production of erythropoietin Erythropoietin injections Does not consider erythropoietin's (local) signaling actions,
which are currently investigated
Calcium/phophate metabolism Dietary measures, vitamin D,
calcium supplements and
phophate binders
Inadequate control or incomplete understanding of
mechanisms leads to vascular calcifications
Hemodialysis Not very effective in removal of body phosphate excess
Dept. Nephrology
A technical device
a. b. c. d.
Glom
TubWaste
Arterialinflow
Venousreturn
Adapted from Nissenson, Blood Purif., 2005.
Dept. Nephrology
Nissenson, Blood Purif., 2005.
A technical device
Dept. Nephrology
Refurbishing the damaged kidney
PerinatalProgramming
FunctionalReprogramming
StructuralReprogramming
Refurbishing
Dept. Nephrology
Refurbishing the damaged kidney
PerinatalProgramming
weeks-2 0 2 4 8 12 16 20 24 28 32 36
mmHg
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Treatment
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SHR con
SHR mol
FHH con
FHH mol*
Dept. Nephrology
Refurbishing the damaged kidney
FunctionalReprogramming
Dept. Nephrology
Refurbishing the damaged kidney
Rookmaaker MB, Tolboom H, Goldschmeding R, Zwaginga JJ, Rabelink TJ, Verhaar MC. Bone-marrow-derived cells contribute to endothelial repair afterthrombotic microangiopathy. Blood. 2002 Feb 1;99(3):1095.
Dept. Nephrology
Refurbishing the damaged kidney
Oliver JA, Maarouf O, Cheema FH, Martens TP, Al-Awqati Q. The renal papilla is a niche for adult kidney stem cells. J Clin Invest. 2004 Sep;114(6):795-804.
Dept. Nephrology
Refurbishing the damaged kidney
Feng, Z, Plati, AR, Cheng, QL, Berho, M, Banerjee, A, Potier, M, Jy, WC, Koff, A, Striker, LJ & Striker, GE: Glomerular aging in females is a multi-stage reversible process mediated by phenotypic changes in progenitors. Am J Pathol, 167:355-63, 2005.
Dept. Nephrology
Refurbishing the damaged kidney
Sketch of the strategy
- Harvest stem cells from patient- Grow these cells on a matrix/scaffold in a healthy environment
- Partially decellularize native kidney
- Transplant ex vivo grown cells/structures into native kidney
Dept. Nephrology
(Partially) grow a kidney in vitro, using therapeutic cloning
Dept. Nephrology
(Partially) grow a kidney in vitro, using therapeutic cloning
(A) Illustration of renal unit and units retrieved three months after implantation. (B) Unseeded control. (C) Seeded with allogeneic control cells. (D) Seeded with cloned cells, showing the accumulation of urinelike fluid.
Dept. Nephrology
The distributed kidney
Henderson’s "Perpetual Hamburger:" Recycling Waste
Gene therapy that uses the mesothelial cells as a site for the placement of nitrogen-fixing metabolic architecture
Presumably urea, uric acid, creatinine, and other organic sources of nitrogen, as well as inorganic toxins such as sulfate, phosphate, and hydrogen, will be consumed to synthesize amino acids, polypeptides, or proteins with energy derived from carbohydrate metabolism.
One may then imagine a "perpetual hamburger" that after initialingestion would in its molecular components be infinitely recycled.
Henderson LW: Future developments in the treatment of end-stage renal disease: A North American perspective. Am J Kidney Dis 35 [Suppl 1]: S106–S116, 2000
Dept. Nephrology
Do we have a dream?
InnovativeRenalReplacementTherapy
The Implantable Device Design membranes using nanotechnologyDesign a deviceScale downDesign connections to circulation and to bladder
The Refurbished Kidney Acquire knowledge about:- Normal repair by stem cells- Homing factors of stem cells- Matrix conditions- Creating a suitable a-cellular matrix (native
or from donor)Provide proof-of-principle in animal models
The Cultured Kidney Acquire more extensive knowledge aboutembryonic development and in vitro growth of organs.Reach agreement about what is an acceptableethical approachAcquire knowledge about the phases when anembryonic implant will be harvested by the host and develop appropriately.
Distributed Renal Functionality Acquire knowledge about regulation of renalhormone regulation.Explore transfection and cellular transplantationtechniques.
Dept. Nephrology
Do we have a dream?
Dept. Nephrology
NephrologyHelena ChonAdèle DijkSebastiaan WesselingFarid KantouhDr Hans BluyssenDr Jaap JolesProf Dr Hein Koomans
Vascular MedicinePeter WesterweelDr Marianne Verhaar
GenomicsDr Frank HolstegePatrick Kemmeren
Royal Dutch AcademyOf Arts and Sciences
DUTCH KIDNEY FOUNDATION
Univ. Med. Center Utrecht