Summary of Fissell's review paper in 2013 International Kidney

Quick review of “Achieving more frequent and longer dialysis for the majority: wearable dialysis and implantable artificial kidney devices” by Fissell, Roy, and Davenport
see Fissell(Roy)_2013_International_Kidney.pdf in the hemodialysis section of the library.

First a little background:
Two type of wearable devices: Peritoneal Dialysis (PD) and Hemodialysis (HD)
In PD, dialysate is pumped into and out of the peritoneal cavity, the blood vessels in the peritoneum do the job of the kidneys filtering the waste to the dialysate in the peritoneal cavity. Only access for the dialysate is required, no blood access. Once a patient suffers form peritonitis, infection of the peritoneum, PD is no longer a choice. This eventually occurs in most patients due to the use of the permanent catheter (dual lumen) which is susceptible to infection. PD can be done at home and requires (30 to 40) min to fill or drain the fluid with 4 exchanges a day with a dwell time of (4 to 6) hours.

In HD, blood access is required, usually with a fistula, a connection from an artery to a vein, usually in the arm. Access points in both vessels are used to deliver blood to the HD device (artery) and return to the body (vein). Grafts are sometimes used. Both can experience problems and a new fistula or graft needs to be created in the next arm, or leg. The blood is then cleared of toxins and excess fluid via extracorporeal filtration which in clinical setting requires peristaltic roller pumps. large filters, large amounts of ultra pure dialysate and monitoring systems. Typical treatments are 3 times a week for 4 hours.

Now on to the paper.
Peritoneal Dialysis:
ViWAK (1) Continuous Peritoneal Dialysis. (continuous dialysate flow with a double lumen one pumps in, one pumps out) A series of sorbents is used to remove most middle molecules proteins, and ions, but urea is not easily adsorbed. urea is metabolized to ammonium and carbon dioxide with the inclusion of urease. The ammonium is adsorbed by zirconium phosphate. Carbon dioxide can generate bubbles so a degassing chamber is required. (pumps can also generate bubbles). Gas can be eliminated from the system with a gas permeable liquid impermeable plastic polymer (2).
Sorbants include microporous carbon, zirconium, polystyrene.
Microporous carbons adsorb creatinine, uric acid, chloramines, oxidants, organic compounds, heavy metals, beta 2 micro globulin, and protein-bound solutes.
zirconium phosphate adsorbs ammonium, calcium, magnesium, potassium and cations and metals.
It also releases other molecules and ions which changes the glucose, bicarbonate, and electrolyte of the dialysate.
The ViWAK does not control for electrolyte changes.
Needs fresh dialysate daily (designed for two exchanges a day) and there is no ultrafiltration control except by adding glucose to the dialysate for the last 2 hours of the daytime cycle.

ViWAK has not been tested in animal or clinical trials.

Hemodialysis
AWAK. dialysate flow is discontinuous (single lumen pumps in then pumps out)
One big concern with miniaturizing HD systems is the pumps which can generate heat and bubbles. Both are bad. as is platelet activation and fouling.
This system has chambers for electrolyte and lactate and glucose. These are used to refresh the dialysate so it can use the same dialysate for up to a month. Initial addition of 750 mL of dialysate to the peritoneal cavity Some dialysate is removed daily, some monthly.
Anticoagulation is required as is active control of ultrafiltration. Control circuits, monitors, mini pumps, feedback loops to control electrolyte, glucose, ultrafiltration etc ate used as are gas permeable plastics to remove carbon dioxide generated by the metabolism of urea by urease.
Safety features to avoid air emboli and blood loss are included.
18 hour rechargeable battery. Extra large sorbent cartridges are used to keep up with the demand. animal studies have been conducted using the pig model. Short term clinical trials (“relatively short duration”) and is being “fast-tracked by the US FDA for further clinical trials”

Nanodialysis, earshot, netherlands also working on wearable HD. as I mentioned in a recent NRG blog post.

Implantable
Self-administered dialysis for home use has drawbacks. Needle phobia and undetected needle dislodgment are the main barriers (3)
Sergeyeva (4) says that in-center patients are slow to adopt home dialysis options such as the NxStage System 1 (NxStage Medical, Lawrence, Massachusetts). Fissell concludes that this may be a good argument for implantable system.
Implantable devices would eliminate most externals including dialysis equipment and consumables. There may still be some external monitoring equipment but these would most likely be noninvasive relying on wireless technologies to communicate with the implanted device. At most monitoring similar to that used by diabetic patients may be required.
Ex vivo blood access would be eliminated in an implantable system so access-associated infections and accidental disconnections would also be eliminated.
Goals: waste elimination and homeostasis of fluid volume.
No pump needed. device is anastomosed to the iliac vessels. (the artery and vein connecting to the kidneys)

The mammalian kidney first filters blood with the glomerulus creating a ultra filtrate plasma. a second filtration (tubule) allows water and a small number of solutes to pass (electrolytes, urea, glucose, amino acids, and small proteins) This concentrates the waste products of (100 to 140) L of filtered blood to be concentrated to a volume of (1 to 2) L, which can be balanced with oral intake.
Standard dialysis requires ~240 L of ultra pure water per treatment.

cardiac pressure: (80 to 100) mm Hg. hydrostatic pressure within device needs to drive 30 mL/min of convective small solute clearance. Fissell believes that elongated pores are called for, the present the steric resistance to large molecules while offering less resistance to fluid flow. He states that not only do glomerular slit diaphragms contain elongated pores, but so do storm drains.
He also states that polymer membranes have a high variability of pore sizes.(5)
These membranes are made with the pore distribution shifted to the smaller pores to reduce the number of large pores to limit protein leakage but at the cost of hydraulic permeability.
This is where he introduces his silicon nano slot technology with pores of (5 to 10) nm in width. They measured hydraulic permeability as well as steric and electrostatic hindrances. (6)
Fissell says that tubule membranes have not yet been developed to differentiate which solutes to pass back to the blood and which to carry away as waste to the bladder.
Humes (7) has grown renal tubular cells on hollow fibers and to confluence on silicon nano porous membranes.
They maintained viability, epithelial integrity, and low insulin leakage was detected. (cells were harvested from renal transplant discards)
Even if this bioartificial device is developed, it would not completely replace natural kidney function and implant patients would still need to rely on medications and dietary modification to maintain homeostasis.

Discussion (a little anyway)
Fissell summarizes the current work on wearable dialysis quite well and mentions nanodialysis (the company I mentioned in a previous post), he does not talk about the work on the Human Nephron Filter (HNF) I had talked about in that same previous post. The difference between his idea of using the bioartificial filter and the “tubule” filter in the HNF paper is that the former is being developed but relies on keeping biological materials alive in vitro and the latter is completely imagined but does not require being kept alive during fabrication.
Current HD devices, including the wearable systems discussed in the paper require a lot of dialysate or need to regenerate the dailysate on the fly. We need to be able to do the same, either adsorb the toxins in small replaceable units and some amount of dialysate pumping through the system. How much depends on how well we can regenerate the dialysate. We also need to get rid of wast fluid. There can be several liters of water removed in a 3 to 5 hour treatment. If we assume 2 liters a day, thats ~110 mL/hr for the duration of an 8-hour treatment (1.78 mL/min).
The other option could be to use the Human Nephron Filter concept with two membranes one to create the ultra filtrate plasma using the 15 nm pore membranes and s second membrane with much smaller pores to allow only the passage of water and salt which is passed back to the blood system.

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1 Ronco C, Fecondini L. The Vicenza wearable artificial kidney for peritoneal
dialysis (ViWAK PD). Blood Purif 2007; 25: 383–388.)
2 Ronco C, Davenport A, Gura V. A wearable artificial kidney: dream or
reality? Nat Clin Pract Nephrol 2008; 4: 604–605
3. Cafazzo JA, Leonard K, Easty AC et al. Patient-perceived barriers to the
adoption of nocturnal home haemodialysis. Clin J Am Soc Nephrol 2009;
4: 784–789.
4. Sergeyeva O¸, Gorodetskaya I, Ramos R et al. Frequent Hemodialysis
Network Trials Group. Challenges to enrollment and randomization of the
Frequent Hemodialysis Network (FHN) Daily Trial. J Nephrol 2012; 25:
302–309.
(5) Zeman LJ, Zydney AL. Microfiltration and Ultrafiltration. Marcel Dekker:
New York, 1996, pp 180–253.
6 Fissell WH, Dubnisheva A, Eldridge AN et al. High-performance silicon
nanopore hemofiltration membranes. J Memb Sci 2009; 326: 58–63.
7 Humes HD, Weitzel WF, Bartlett RH et al. Initial clinical results of the
bioartificial kidney containing human cells in ICU patients with acute
renal failure. Kidney Int 2004; 66: 1578–1588.

NOTES:
*Three main ions that can be found in the plasma are calcium (Ca2+), magnesium (Mg2+) and sodium (Na+)
*Medications and dietary modification can help compensate for the loss of some of the physiological functions of the mammalian kidney.
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References of interest
Hofmann CL, Fissell WH. Middle-molecule clearance at 20 and 35 ml/kg/h
in continuous veno-venous haemodiafiltration. Blood Purif 2010; 29:
259–263.
Messer J, Mulcahy B, Fissell WH. Middle-molecule clearance in CRRT: invitro
convection, diffusion, and dialyzer area. ASAIO J 2009; 55: 224–226.