Roadmap towards future renal replacement therapy and the

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


PerinatalProgramming

weeks-2 0 2 4 8 12 16 20 24 28 32 36

mmHg

100

120

140

160

180

200

220

**

**

# # #

Treatment

*

SHR con

SHR mol

FHH con

FHH mol*

Dept. Nephrology


FunctionalReprogramming

Dept. Nephrology


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


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


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


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

Documents

Roadmap towards future renal replacement therapy and the