2. Assessing Peritoneal Barrier Function Role of the PET in Ongoing Management of PD Patients
Ali K. Abu-Alfa, MD, FASN
Professor of Medicine
Head, Division of Nephrology and Hypertension
Director, Human Research Protection Program
American University of Beirut
Beirut, Lebanon
Mashhad
Iranian Society of Nephrology
September 2015
Middle East Chapter

3. Questions from a Clinical Perspective: Functional Tests
Do functional tests for interrogating the peritoneal barrier help us with clinical management?
Do these tests change over time and do they correlate with membrane changes?
Can functional tests help predict the development of Encapsulating Peritoneal Sclerosis (EPS)?

4. Approach Review relevant underlying physiologic principles.
Discuss functional clinical tests:
Peritoneal Equilibration Test (PET).
Highlight derived clinical parameters:
Solute transport, mass transfer and clearances
Fluid removal: Sodium sieving, osmotic conductance.
Review longitudinal changes in peritoneal barrier function and histology.

5. Peritoneal Barrier Transport
Peritoneal Dialysis is a direct illustration of the clearance concept.
Feasibility of having repeated collections of an entire dialysate volume, per unit time (typically 4 to 24 hours), permits calculation and derivation of many clinically useful parameters.
These parameters have been extensively utilized in modeling and computerized prediction programs.
PET is a standard established assessment tool.

6. Peritoneal Barrier Function: Functional Tests Used
TEST Name/Goal
Parameter used to evaluate solute removal function
Parameter used to evaluate fluid removal function
Peritoneal Equilibration Test
(4-hours standard 2.27/2.5% PET)
D/P creatinine, MTAC D/D0 glucose
Drain volume
Dialysis Adequacy and Transport Test (24-hour, DATT)
D/P creatinine
Drain volume
Standard Permeability Analysis (SPA)
MTAC creatinine
Drain volume, D/P sodium, D70, Restriction Coefficient
Personal Dialysis Capacity (PDC)
Area parameter Ao/Δx
Drain Vol, LpS, JvAR, JvL
APEX
D/P Urea and D/D0 vs time
APEX time
D/P Na, Drain Volume
FWT, UFSP, OCG
Ultrafiltration Analysis
MTAC: Mass Transfer Area Coefficient Ao/Δx: Area Parameter
FWT: Free Water Transport LpS: Hydraulic Conductance
UFSP: UF Small Pores JvAR: Re-absorption parameter
OCG: Osmotic Conductance Glucose JvL: Large Pore Flow parameter
Adapted from Teitelbaum I et al, Peritoneal Dialysis, in Schrier Diseases of the Kidney and Urinary Tract, 2004

7. Structure of the Peritoneal Membrane

8. Physiology of Ultrafiltration: Normal Human Peritoneum
RBCs
Endothelium
Interstitium
Mesothelium
Adapted from Lai et al: J Am Soc Nephrol 2001: 12: 1036–1045

9. Distributed Model Concept
Flessner MF. J Am Soc Nephrol 1991: 2; 122

10. Three-pore model Endothelium = Osmotic P = Hydraulic
Rippe et al: Microcirculation 2001: 8, 303–320

11. Peritoneal Barrier Function: Clinical Parameters of Interest
PDC: Personal Dialysis Capacity
PET: Peritoneal Equilibration Test
Heimbürger O: Contrib Nephrology 2009: 163; 82-89

12. Peritoneal Barrier Assessment: Clinical Functional Tests
Peritoneal Equilibration Test (PET)
Standard PET, Fast PET
Modified or High Glucose 3.86% PET
Mini-PET
Double Mini-PET
Dialysis Adequacy and Transport Test (DATT)
Accelerate Peritoneal Exchange Time (APEX)
Peritoneal Dialysis Capacity (PDC)
Standard Permeability Analysis (SPA)

13. Standard Steps for Peritoneal Equilibration Test (PET)
The CaR is the principal regulator of PTH secretion.
Activation of the CaR by an increase in extracellular calcium produces a rapid decrease in PTH secretion—occurring within minutes or hours. A decrease in extracellular calcium produces a rapid increase in PTH secretion.
In contrast, vitamin D sterols inhibit PTH production rather than secretion, and response to therapy with vitamin D sterols is therefore slower than response to calcium.
Adapted from Twardowski et al.: Peritoneal Dial Bull 1987, 7: 138–147
Chen MC et al. Chang Gung Med J 2010: 33;

14. Peritoneal Equilibration Test (PET)
Creatinine
Glucose
D/P
D/Do
1.2
1.2 1 1
Low
L Ave
H Ave
High
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
The CaR is the principal regulator of PTH secretion.
Activation of the CaR by an increase in extracellular calcium produces a rapid decrease in PTH secretion—occurring within minutes or hours. A decrease in extracellular calcium produces a rapid increase in PTH secretion.
In contrast, vitamin D sterols inhibit PTH production rather than secretion, and response to therapy with vitamin D sterols is therefore slower than response to calcium. 1 2 3 4 1 2 3 4
Twardowski et al.: Peritoneal Dial Bull 1987, 7:138–147.

15. Distribution of PET in North America
The CaR is the principal regulator of PTH secretion.
Activation of the CaR by an increase in extracellular calcium produces a rapid decrease in PTH secretion—occurring within minutes or hours. A decrease in extracellular calcium produces a rapid increase in PTH secretion.
In contrast, vitamin D sterols inhibit PTH production rather than secretion, and response to therapy with vitamin D sterols is therefore slower than response to calcium.
Mujais S, et al. Kidney Int. 2002: 62; s81, S17-S22

16. Clearance versus Mass Transfer
The product of dialysate volume drained per unit time * D/P (Dialysate/Plasma) ratio of a solute is simply the clearance for that solute.
A D/P creatinine of 0.7 will yield the same unadjusted creatinine clearance values of 7.7 L/day for 11 liters of total drained dialysate volume on CAPD:
For patient A with BSA 1.6 m2, CrCl = 58 L/week/1.73m2
For patient B with BSA 1.9 m2, CrCl = 49 L/week/1.73m2
Mass Transfer for patient A = mg/day (SCr=7)
Mass Transfer for patient B = 1110 mg/day (SCr=10)

17. Peritoneal Barrier Transport: Membrane Determinants
Van Biesen W et al: Nephrol Dial Transplant 2003: 18;

18. Peritoneal Barrier Transport: Underlying Basic Principles
Rate of diffusion across the membrane is determined:
Diffusive permeability of the solute or the ratio between the free diffusion coefficient (D) and diffusion distance (Δx)
Surface area (A0) available for transport: number of perfused capillaries, pore number, pore size:
Pore Restriction Factor (P = Am/A0 )
Concentration gradient (ΔC)
Permeability Surface Area Product = D / (Δx) * A0 * P
PS is same as Mass Area Transfer Coefficient (MTAC).
Rate of diffusion is then: MTAC * (ΔC)
Krediet R in Replacement of renal function by dialysis 4th Edition
Haraldsson J: Kidney International 1995: 47;

19. Peritoneal Barrier Transport: Area Parameter A0/Δx
Area Parameter (A0/Δx) determines the diffusive capacity for small molecules across the peritoneal barrier for an individual patient.
It reflects the total area available for diffusion over the diffusion distance and is thought to be a more general parameter than PS or MTAC, which in fact it defines.
It can be derived based on five different determinations of dialysate concentrations and is potentially more accurate than the standard PET.
Its determination is an integral part of the PDC test.
Heimbürger O: Contrib Nephrology 2009: 163;
Johansson C and Haraldsson J. PDI 2006: 26;

20. Peritoneal Transport Status: Area Parameter Ao/Δx vs PET
Heimbürger O: Contrib Nephrology 2009: 163; 82-89
Johnson E et al: Kidney International 2000: 58; 1773–1779

21. Peritoneal Barrier Transport: Area Parameter and Fill Volume
Johnsson E et al: Kidney International 2000, 58:

22. Peritoneal Barrier Transport: Mass Transfer Area Coefficient
Mass Transfer Area Coefficient (MTAC) is a calculated parameter for each solute that reflects its diffusive transport across the peritoneal barrier based on its thickness and functional surface area.
The rate of this transport is determined by the MTAC and prevailing concentration gradient.
MTAC is independent of convective transport and solute concentration.

23. Peritoneal Barrier Transport: Mass Transfer Area Coefficient
It can be derived from values obtained during standard sampled dialysate collections.
It is used in programs for estimation of clearances upon changes in regimens, including fill volumes.
It has limitations:
It is affected by fill volumes.
It is assumed to be stable over time unless recalculated based on repeat test collections.
Predictions can thus be scientifically inaccurate although clinically useful with rather inconsequential variability in estimates in most instances.

24. Mass Transfer Area Coefficient: Effect of Fill Volume
Peritoneal Instilled Volume Tolerance (PIVOT) Study
n=19 using 2.5% PET with hourly sampling of dialysate
Statistically significant increase in MTACs for Urea and Creatinine (ANOVA, p < 0.05)
Abu-Alfa A et al: ASN 2001
Keshaviah P et al JASN 1994; 4:

25. Physiology of Ultrafiltration: Structure of Peritoneal Barrier
H2O
Capillary
Peritoneal Space
Glucose
Aquaporin mediated: 50%
Glucose transporter mediated: minimal
Intercellular: 50%
Intercellular: >90%

26. Sodium Sieving with 3.86% Glucose
LaMilia et al, Nephrol Dial Transplant (2004) 19:

27. Glucose exposure (grams/year) (D/P creatinine at 4 hours
Physiology of Ultrafiltration: Changes in Transport Profile
Glucose exposure (grams/year)
Time on Treatment
This is a landmark retrospective analysis by Dr Davies. It shows that incident patients followed 2 different courses over 5 years. Both groups started with the same D/P creatinine ratio or similar membrane transport types. One group evolved a higher transport profile in about 2 years, and those patients required higher glucose concentrations in the first 2 years. This could be the result of loss of residual renal function, dietary indiscretion, etc… It highlights the importance of early efforts to preserve RRF, the use of diuretics, a lower Na intake and reduced use of higher concentration glucose solutions.
(D/P creatinine at 4 hours
Solute Transport
Davies et al. J Am Soc Nephrol. 2001: 12; 27

28. Changes in Transport Profile: CAPD Cohort - Taiwan
CAPD, all Dextrose-based regimen over 16 years
108 non-diabetic patients studies with yearly PET
Chen MC et al. Chang Gung Med J 2010: 33; 28

29. PET 3.86%: Changes in MTAC and Na Sieving after 1 year
Clerbaux G et al: Nephrol Dial Transplant 2006: 21; 1032–1039

30. High Glucose 3.86% PET: UF Failure: Changes over Time
Krediet R et al: Contrib Nephrology 2009: 163; 22-26

31. Compact Sub-mesothelial Zone
Morphologic Changes in Peritoneal Membrane: Peritoneal Biopsy Registry
Normal After 9 years of PD
After a brief overview of the population at risk, we will review the latest understanding of the pathophysiology of secondary HPT.
Traditionally, the emphasis in therapy has focused on suppression of parathyroid hormone (PTH) levels to prevent or treat renal bone disease. Today there is a growing awareness of the need to maintain tight control of mineral homeostasis (Block, Port 2000). Sustained disturbances of calcium and phosphorus metabolism have been linked to increased risk of cardiovascular calcifications (even in young adult end-stage renal disease [ESRD] patients) (Goodman 2000/1479) and to an increased risk of cardiovascular and all-cause morbidity and mortality.
We will review the benefits and risks of current therapies and explore the evidence underlying some of the National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K/DOQI) Guidelines, scheduled for release in In recognition of the growing concern about consequences of disturbances in mineral metabolism, these guidelines are expected to highlight the need for improved control of calcium and phosphorus levels.
Finally, discovery of the calcium-sensing receptor (CaR) is a highly significant advance, which has resulted in development of an entirely new class of agents—calcimimetics. An overview of the CaR and calcimimetics provides an introduction to a potential future therapy.
Block GA, Port FK. Am J Kidney Dis. 2000;35: Goodman WG et al. N Engl J Med. 2000;342:
Compact Sub-mesothelial Zone
Peritoneal Biopsy Registry
20 Centers, 63% cases at Cardiff
130 PD patients
Williams JD et al: J Am Soc Nephrol 2002; 13: 470–479

32. 7.5% Icodextrin versus 4.25%: Membrane Changes in Rat Modela
Groups
C1 a
C2 b
G c
I d
The use of Icodextrin was associated with lower degrees of peritoneal fibrosis as compared to 4.25% glucose solution, and at a comparable to unexposed diabetic rates with 5/6 nephrectomy. This again demonstrates the effect of uremia on the peritoneal membrane per se, and the accentuation of this effect with the use of hypertonic glucose.
Nakao A et al: Nephro Dial Transplant 2010: 25; 32

33. Peritoneal Barrier Assessment: Clinical Functional Tests
Peritoneal Equilibration Test (PET)
Standard PET, Fast PET
Modified or High Glucose 3.86% PET
Mini-PET
Double Mini-PET
Dialysis Adequacy and Transport Test (DATT)
Accelerate Peritoneal Exchange Time (APEX)
Peritoneal Dialysis Capacity (PDC)
Standard Permeability Analysis (SPA)

34. High Glucose 3.86% PET: Recommended for UF Volume
Loss of UF capacity defined as < 400 ml after a 4 hrs 3.86% dwell.
No effect on D/P ratios or standard classification of transport status
Pride E et al: PDI 2002: 22;
Mujais D et: PDI 2000: 20 Suppl2: S5-S21

35. Mini-PET (1 hr) 3.86% versus Full PET (4 hrs) 3.86%
La Milia E et al: Kidney International 2005; 68: 840–846

36. Peritoneal Barrier Fluid Transport: Ultrafiltration Analysis
La Milia V et al: Kidney International 2007: 2;

37. Peritoneal Barrier Fluid Transport: Ultrafiltration Analysis
Free Water Transport (FWT) and Ultrafiltration Small Pores (UFSP) were calculated using 2 Mini-PET:
Each mini-PET lasted 1 hour
Sequential use of 1.36% AND 3.86%
Na diffusion is main parameter used for calculations.
La Milia V et al: Kidney International 2007: 2;

38. FWT and UFSP: Clinical Use Patients with UF Failure (UFF)
La Milia V et al: Kidney International 2007; 72:

39. Na Sieving: Clinical Use Patients with UF Failure (UFF)
Gomes AN et al. NDT 2009 : 24; 3513–3520

40. Encapsulating Peritoneal Sclerosis Pre-EPS Changes in UF Capacity
Lambie ML et al.. Kidney International 2010: 78; 611–618

41. Encapsulating Peritoneal Sclerosis Pre-EPS Changes in MTAC
Sampimone D et al. Nephrol Dial Transplant 2011: 26:; 291–298

42. Encapsulating Peritoneal Sclerosis Pre-EPS Changes in UF & MTAC
Morele J et al. J Am Soc Nephrol 2015: 26, ePub

43. Encapsulating Peritoneal Sclerosis Pre-EPS Changes in Na Sieving
Morele J et al. J Am Soc Nephrol 2015: 26, ePub

44. Encapsulating Peritoneal Sclerosis Predictive Value of Na Sieving
Morele J et al. J Am Soc Nephrol 2015: 26, ePub

45. Encapsulating Peritoneal Sclerosis Increased Vascularity and Fibrosis
Morele J et al. J Am Soc Nephrol 2015: 26, ePub

46. Encapsulating Peritoneal Sclerosis Na Sieving and UF vs Fibrosis
Morele J et al. J Am Soc Nephrol 2015: 26, ePub

47. Encapsulating Peritoneal Sclerosis Fibrotic Interstitium as Core Issue
Interstitial fibrosis acts
as a second resistance, in series with the capillary wall, and markedly reduces the UF coefficient of the membrane, contributing to the
loss of sodium sieving and free-water transport, despite the fact that the capillary ac (i.e., AQP1 density) remains unchanged.
Morele J et al. J Am Soc Nephrol 2015: 26, ePub

48. Conclusions
Peritoneal Barrier can be clinically assessed in a multitude of approaches of varying complexity.
Most clinical information can be gleaned from a simple PET, mini-PET or high -glucose modified PET.
Understanding the underlying physiologic principles permits a more sophisticated interpretation of values.
Parameters change over time and repeat assessments appears to be helpful to detect early changes in UF, and thus assess the risk for development of EPS.