Physiological function of pd

Physiological Basis of PD

By Dr Ahmed Salah Younes

Nephrologist at Rustaq Hospital

An understanding of membrane physiology is required for proper determination of the PD

prescription . Dr .steven Guest

The basics of dialytic therapy was laid down by:Thomas Graham (1805-1869).

◦ He described the Graham’s Law, investigated on osmotic forces, separated fluids by “dialysis” and also differentiated crystalloids from colliods.

◦ “Father” of modern dialysis.

René Dutrochet (1776-1846): introduced the term “osmosis” which explains ultrafiltration.“Grandfather” of dialysis.

Recklinghausen, Wegner, Beck, Kollossow (Later half of 19th century) described the mesothelium, transport of solutes and water across the peritoneum & also described the pathways of transport.

Starling & Tubby(1894) described that solute transport was primarily between Peritoneum Cavity and blood (lymphatic transport was negligible).

Cunningham, Putnam & Engel (Early 20th century) described the role of peritoneal membrane as a “dialyzing membrane”.

History of PD

Georg Ganter (Germany, 1923) was the first person who applied PD in humans. He published his work in his paper: “On the elimination of toxic substances from the blood by dialysis”.

Interestingly, he made many observations that are still valid:◦ An adequate access was needed.◦ Infection was the most imp. complication.◦ Large volume of fluid was needed (1-1.5L).◦ Dwell time was needed for equilibrium.◦ Hypertonic solutions were needed to promote fluid and toxin

removal.

Histoery of PD

Richard Ruben (San Fransisco, 1959): he was the first to initiate long term IPD in CRF. The first patient was Mae Stewart, 33/F.

Boen (Seattle, 1962): ◦ First long term PD programmed.◦ First automated PD machine.◦ Repeated puncture method using “Boen’s button.”◦ develop fluid factory ,◦ explain diffusion curve , ◦ peritoneal clearance , ◦ described the influnce of glucose on ulterafilteration◦ modeled the correction of metabolic acidosis with add of

bicarbonate to fliud ,◦ He develop completely closed system with limit the risk of

infection ◦ He designed larger infusion bottles to allow for repeated

infusion , monitor fluid removed he automated the entire PD system at home

Histoery of PD

The PD take place between the blood in the capillary located in intersteium of the peritonium and infused dialysis solution across peritoneal membrane

The peritoneal membrane serves as dialyzing membrane that can allow solutes to move from the capillary blood compartment to the dialysate in the peritoneal cavity

The peritoneal membrane act as semipermeable membrane had a surface area about 1 to 2 m2

The total membrane area includes the visceral peritoneum (60%) , peritoneal covering the mesentery and omental surfaces (30%) , and the parital peritoneum (10%)

Introduction

The peritoneal membrane has an extensive blood supply

1. The visceral peritoneum supplied by mesenteric arteries that drain ultimately into the portal circulation

2. The parietal peritoneium supplied by smaller epigasteric , intercostals and lumber arteries that drain directely into inferior vena cava the estimated total peritoneal blood flow is 50 to 100 ml/min

Blood supply

Three major peritoneal components could filter toxins from the blood compartment into peritoneal space :

1- Mesothelial cell layer 2- Interstitial space 3- Capillary endothelium and basement

membrane (most important to determined solute transport )

The parietal peritoneum is more important in transport than the visceral as only 25-30 % of the viscarl peritoneum it is in contact with the peritoneal fluid.

Barrier of peritoneal membrane

Several theoretical constructs have been described to help determine the transport of solutes across the peritoneal capillary bed .

three of the most discuss models are the :1- The distributed model2- Three pore model3- Pyle – popvich model

Model of peritoneal transport

1- The distributed model of peritoneal transport

The distributed model is used largely in the research setting and is much more complicated , mathematically , and not used clinically

In the distributed model , capillary are described as being distributed throughout the peritoneal membrane and are at variable distance from peritoneal cavity ,


Solute transport is therefore affected by the blood dialysate distance (the amount of intersitium ) ,


2- Pyle –popvich model The Pyle-popovich model , the physiological reality

is simplified by considering just two homogeneous compartments (body and dialysate) separated by an ideal homoporous semi-permeable membrane with constant characteristics and nil thickness.

Treats the peritoneal membrane similarly to a hemodialyzer membrane .

The mass transfer area coefficient (MTAC) : is determined without taking into consideration the specific anatomic factor such as the interstitium or capillaries


3- Three pore model of peritoneal transport : The most commonly discussed clinical

model is the three pore model . In the three pore model , the main barrier

to solute transport is the peritoneal capillary .

The capillary endothelial cells are descirbed as having 3 pores that allow for movement of solute and water across the capillary .

These three pores are the transcelluler aquaporines , small and large pores


1) The aquaporins allow for only water transport across the cell and a complete barrier to any solute transport across this pore. Aquaporine are stimulated by dialysate osmolalityand are open when expose to osmotically active dextrose solutions.

2) The small pores likely represent inter endothelial clefts that allow for transport of small solutes such as urea , Na , K and creatinine dissolved in water .

3) The large pores allow for transport of larger macromolecules such as proteins.


The pores have the following ch.ch. :


Denisity Size Pores

Large R=4-5 angstroms Aquaporines(AQP1)

Large R=40-50 angstroms Small pores

Small R=>150 angiostroms Large pores



The three pore model allows for an understanding of the movement of water and solutes of varying size

This transport occurs due to two physiological processes that occur simultaneously :

1- Solute removal A- Diffusion B- Convection 2- Fluid removal

Ulterfilteration


Diffusion

Ulterafilteration Convection


Diffusion : the predominant mechanism of small solute

transport in PD . Diffusion clearance is dependent on many factors :1- The effective peritoneal membrane surface area 2- The solute concentration gradients from blood to

dialysate 3- The dwell time of dialysate in the peritoneal cavity 4- Solute characteristic 5- The dialysate flow rate


Diffusion occurs from the blood into the dialysate as well as from the dialysate into blood .

example , uremic toxins diffuse down , a concentration gradient into the dialysate while dialysate lactate and glucose diffuse into the capillary blood supply .

Substances with smaller molecular weight diffuse more rapidly than those with larger moleculer weight .


Urea diffuse more rapidly than creatinine or middle molecules .

Peritoneal diffusion of solute can vary patient to patient and are determined by the vascularity of peritoneal membrane and inflammatory state.

Kinetic of diffusion solute transport Accordinto the Fick’s Law, is :


Js=(Df/Δx).A.ΔC

Where :Js=rate of solute transport,Df=diffusion coefficient,Δx=diffusion distance,A=Surface area,ΔC=concentration gradient.

MTAC The “Permeability surface area cross product” or the “MassTransfer Area Coefficient (MTAC)”

Is theoretically equal to the diffusive clearance of a solute per unit time when the dialysate flow is infinitely high so that the solute gradient is always maximal”.

Or in EnglishTheoretical maximal clearance of a solute at time zero


Js=(Df/Δx).A.ΔC

MTAC values of small molecular weight substances are representative of the functional surface area.

Restriction coefficient on the other hand is a representation of the size-selectivity.

MTAC values:1. Urea=17mL/min.2. Creatinine=10mL/min The D/P ratio has a good correlation with

the MTAC values


Convection: Convection occurs when dissolved solutes are

small enough to move through the pores as water is moving across the capillary , in response to an osmotic force .

More specifically , as dialysate glucose creates an osmotic force that attracts water from the capillary blood space , solutes that are dissolved in that water move into the dialysate , resulting in clearance of those solutes from the blood by this convection process often called (solute drag)

Model of peritoneal transportv

Middle molecules such as B2-microglobulin move into the peritoneal cavity predominant by convection .

The combined diffusive and convective clearance of molecules can be modeled over varying time points



Ulterafilteration : Ulterafilteration refer to the process of fluid

movement across the peritoneal membrane in response to osmatic force

Ultrafilteration occurs across both the aquaporins and the small pores ,

aquaporin mediated water movement accounting for 40-50%of total ulterafilteration and the small pores accounting for 50-60% of the total ulterafilteration .


Ulterafilteration volume can be modified by use of different osmotically active PD solution , lower osmatic solutions (1.5%dextrose concentrations) can create a peak ulterfilteration of over one hundered ml . higher osmatic forces (4.25% dextrose ) result in larger movements of ulterafilteration

As dextrose is absorbed across the peritoneium and enters the capillary the osmatic gradient slowly dissipates, resulting in cessation of net ulterfilteration and re-absorption of dialysate

we can conclude that icodextrin, due to to its high molecular weight induces colloid osmosis even when it is a iso-hypoosmotic solution.

This movement of fluid takes place through the “small pore system”.

Due to the hypo-osmolality of this solution, no movement of fluid takes place through the ultra-small pores and hence there is “No Sieving with Icodextrin”.



Lymphatic fliud absorption : Fliud in the peritoneal cavity can be absorbed via the

lymphatic vessels Lymphatic vessels are predominantly in the sub-

diaphragmatic location and have transport rates of 1-2 ml/min up to 2 L/day that can vary by the degree of intraperitoneal hydrastatic pressure ,

hydrastatic pressure is positional , with the greatest intra-abdominal pressure created in the sitting position compared to lying position .

The net fluid removal on PD is therefore , the transcapillary ulterafilteration, in response to the dialysate osmatic force minus the lymphatic reabsorption that has occurred



Sodium sieving : Aquaporine allow for up to 50% of total

water movement across the capillary endothelium and by definition theses pores allow for only water movement without solute.

Therefore , any solute dissolved in the water is held back or sieved at the aquaporine .

.


rapid movement of water across the aquaporins, as can occure with rapid cycling of PD fluid with an automated cycler device , can result in significant sieving of sodium (a build up of sodium in the capillary ) result relative hypernateremia and increase thirst may nullify the expected benefits of ulterafilteration .

The degree of sodium sieving (and aquaporine function) can be determined by measuring the sodium concentration in the dialysate .


The initial dialysate sodium concentration 132mEq/L is usual diluted by pure water movement across the aquaporins .

Dialysate sodium concentration can fall to approximately 120mEq/L in the first few hours of dwell .

A failure of dialysate sodium to decrease during this time is evidence of aquaporine deficiency , and is useful in the investigation of ulterafilteration failure.

Aquaporine are stimulated by the osmolality of the dextrose containing solution ,

Aquaporine are not activated by iso-osmolar icodextrine solution . sodium sieving has not been described with icodextrin .


Patient on longer term PD therapy are noted to develop many alterations in the peritoneal membrane.

Over time mesothelial cell mass is reduced. mesothelial cells were noted to undergo Epithelial

to mesenchymal transition (EMT )with mesothelial cells transforming to fibroblastic cell lines.

The new fibroblasts migrate to submesothelial location and growth factors such as transforming growth factor - B , resulting in an expansion of sub-mesothelial connective tissue (the subcompact zone).

Peritoneal membrane changes during long term PD therapy

Increased numbers of peritoneal capillary were noted .

These vascular changes appear to the result of dialysate –induced increases in vascular endothelial growth factor (VEGF).

In patient demonstrating these vascular changes , the movement of solutes can be increased , resulting more rapid peritoneal membrane transport status and increased absorption of glucose , with loss of ultrafilteration capacity .


Monitoring long term peritoneal membrane transport status is recommended and if significant changes are detected the PD prescripitrion will required adjustment .


Fluid removal in clinical practice can be enhanced by

1. Maximizing the osmotic gradient.1. Higher tonicity dwells.2. Shorter duration dwells (eg. APD).3. Higher dwell volumes.

2. Using osmotic agents with higher reflection coefficients (eg. Icodextrin).

3. Increasing urine output (eg. Duiretics)

Application of physiology

Peritoneal Clearance of solute which is the net result of diffusion plus convective clearance minus the absorption can be increased by:

1. Maximizing time on PD (no dry dwells).2. Maximizing concentration gradient.

1. Frequent exchanges2. Larger dwell volumes

3. Maximizing effective peritoneal surface area.

4. Maximizing fluid removal.

Application of physiology

Health & Medicine

Physiological function of pd