Basics of peritoneal dialysis

1. Dr. Vishal Golay 14-03-2012 Basics of Peritoneal Dialysis

2. Topic overview History of evolution of CAPD. Anatomy of the peritoneum. Physiology of the peritoneum with respect to CAPD. Peritoneal Equilibrium Test.

3. “If you would understand anything, observe its beginning and its development.” -Aristotle

4. History of Peritoneal Dialysis 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.

5. Recklinghausen, Wegner, Beck, Kollossow (Later half of 19 th 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 PC and blood (lymphatic transport was negligible). Cunningham, Putnam & Engel (Early 20 th century) described the role of peritoneal membrane as a “dialyzing membrane”.

6. First attempt at 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.

7. Early attempts at PD Howard Frank, Arnold Seligman & Jacob Fine (USA, 1946): intermittently continuous irrigation of the peritoneal cavity. Arthur Grollman : used only one plastic catheter and his PD was done intermittently.

8. Modern Era of PD Morton Maxwell (1959): made many new developments that paved way for modern PD. Paul Doolan (1959): PVC catheters. Special PD fluid: Na-140mEq/L, Cl-101mEq/L, Ca-4mEq/L, Mg-1.5mEq/L, Dextrose-15g/L, Lactate-45mEq/L Nylon catheter

9. Advent of the era 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 programme . First automated PD machine. Repeated puncture method using the “ Boen’s button.”

10. Advent of the era of CAPD Tenckhoff (1968): Developed the revolutionary “ Tenckhoff catheter” that changed the PD practice worldwide. Moncreif & Popovich (Austin, Texas; 1975): initiated patients on “continuous mode of PD” and named it CAPD. Ann Intern Med 1978; 88(4): 449-55 Oreopoulos (Toronto Western Hospital, 1977): Adapted the M&P method to their programme and used the plastic bags (wearable bag system with the “spike system”).

11. Advent of the era of CAPD Uberto Buoncristiani (Italy, 1980): he paved way for the most accepted modern form of CAPD, the “Y-set” with the “flush before fill” technique giving rise to the latest sytem : “the disconnect system”, that significantly reduced incidence of peritonitis. Bazzato (1980): Double bag system. Diaz- Buxo (1981): developed APD/CCPD

12. Anatomy of the peritoneum

13. Peritoneum is a serous membrane, derived from the mesenchyma . It is composed of the parietal and visceral peritoneum that lines the peritoneal space. The total surface area of the peritoneum in adults is 1-2m² and the peritoneal space contains 50-100mL of fluid.

14. Visceral peritoneum: Comprises 80% of the TSA. Supplies by the SMA and drains into the portal circulation. Parietal Peritoneum: Comprises 20% of the TSA. Supplied by the lumbar, intercostal & epigastric arteries and drains into the IVC.

15. Natural functions of the peritoneum Facilitate motion Minimize friction. To conduct vessels and nerves to the viscera. Solute transfer and exchange. Regulation of fluid dynamics and UF .

16. Blood vessels Interstitium Mesothelium

17. Mesothelium It consists of a single layer of flattened cuboidal cells (30,000cells/cm²) lying on a basement membrane. Microvilli present on the luminal side increases the effective surface area of the peritoneal cavity up to 40m². Tight junctions and desmosomes are present between the mesothelial cells. Transport through the mesothelium occurs via endocytosis , transcytosis and potocytosis ( caveolae with PI anchors)

18. Interstitium Consists of cells (pred. fibroblast) & fibers (pred. collagen) embedded in an amorphous substance. Thickness of the interstitium varies from 1-2µm to ≥30µm. This thickness influences transport characteristics as this also defines the distance between the mesothelium and bv’s . Movement of solute is determined by the difference in concentration per unit distance ( Fick’s law of diffusion ). GAG’s and glycoproteins also influence solute transport.

19. Peritoneal microcirculation. -Resistance vessels. -Regulation of blood flow to capillaries. Solute and fluid exchange ( principle site) -Leukocyte adhesion -Permeability under inflammatory conditions

20. Peritoneal blood flow ˜ 50-100mL/min. Peritoneal clearance is not blood flow limited as long as blood flow is >30% of normal. Similarly UF also does not appear to be blood flow limited. Vasoactive agents can affect peritoneal clearance by means of capillary recruitment & increasing the micropore diameters. PDF is also vasoactive and causes increased blood flow and capillary recruitment (GDP, lactate)

21. In addition to the vascular network, there is also a system of lymphatics that drain the peritoneum. There are direct stomatas in the diaphragmatic peritoneum as well as lymphatics in the abdominal wall.

22. Physiology of Peritoneal Dialysis

23. Barriers of peritoneal transport There are three main barriers to peritoneal transport of solutes and fluid: Mesothelium . Interstitial tissue. Blood vessels (endothelium & basement membrane) The parietal peritoneum is more important in transport than the visceral as only 25-30% of the VP it is in contact with the peritoneal fluid.

24. Bidirectional transport

25. Models of Peritoneal transport : The Pyle– Popovich model In this 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. By applying irreversible thermodynamic laws, an equation describing the mass transfer rate is obtained. The mathematics was simple but multiple samplings were necessary making this a laborious procedure.

26. Models of Peritoneal transport : The three pore model. It was evident that transport of solutes and fluid was taking place across various clefts between the endothelial cells. However, it was being noted that there was a discrepancy between the Sieving coeff and the Reflection coeff which gave rise to the theoretical possibility of the presence of “water conductive” ultrasmall pores that tended to “sieve back” solutes. For homoporous membrane, this relationship is S=1-RC. However for glucose, S is 0.6-0.7 and RC is 0.02-0.05.

27. The three pore model. Aquaporin-1 Inter-endothelial cleft Large Inter-endothelial clefts

28. Yang et al. Am J Physiol 276 : C76 –C81, 1999

29. Models of Peritoneal transport : The distrubuted model. The previous two models gave a simplistic 1D view of the peritoneal transport but mathematical calculations were easy. However, the distributed model gives a 2D concept including the distribution of capillaries in the submesothelium EFFECTIVE PERITONEAL SURFACE AREA

30. The distrubuted model. The distributed model is closest model to describe the transport physiology. But it is severely limited by the cumbersome calculations of partial differential equations with several variable parameters for a time-dependent solution which makes it difficult to be applied in the bedside and is thus limited as a research tool.

31. Problems with the mathematical models They are empiric in nature and do not describe the physiological situation. It does not take into account the presence of “absorption” of fluid into the tissues. These models assume that there is no tissue surrounding the capillaries while it is not so. The role of the interstitium is totally neglected. The changes in the gradients with time as well as with the distance from the cavity is not fully represented.

32. The two aspects of peritoneal transport 1. Solute clearance. Diffusive. Convective. 2. Fluid removal ( Ultrafiltration )

33. Factors that influence solute diffusion Concentration gradient. Effective peritoneal surface area. Intrinsic membrane permeability characteristics. Solute characteristics. Blood flow (no significant role). Dwell time and total volume of the dialysate . DIFFUSION

34. Kinetics of diffusive solute transport According to the Fick’s Law , Where Js=rate of solute transport, Df =diffusion coefficient, Δ x=diffusion distance, A=Surface area, Δ C=concentration gradient. ( Df / Δ x ).A is the “Permeability surface area cross product” or the “Mass Transfer Area Coefficient (MTAC)” Js=( Df / Δ x) .A. Δ C “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 English…… Theoretical maximal clearance of a solute at time zero

35. This MTAC is calculated by the “Henderson and Nolph ” equation: MTAC=( Vt /t) ln ((P-D0)/(P- Dt ))

36. Size-selectivity of diffusion. The second important influence on the kinetics of diffusion after the concentration gradient is the size of the diffusing solute (inverse relationship). This is often expressed by the term restriction coefficient , in which a value of 1.0 implies absence of a size restriction barrier. Thus, the higher the value of the restriction coefficient , the lower the size-selective permeability of the peritoneum .

37. In summary, 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: Urea=17mL/min. Creatinine =10mL/min The D/P ratio has a good correlation with the MTAC values

38. Determinants of convective transport “Sieving” occurs due to the presence of the ultrasmall pores which holds back the solutes and thus limiting the convective clearance due to UF. This is measured by the “Sieving coefficient” (S) which represents the ratio between the concentration of the solute in the ultrafiltrate and its concentration in the plasma, assuming that net diffusion is zero. S ranges from 0(complete seiving ) to 1(no sieving).

39. Determinants of Ultrafiltration Concentration gradient of the osmotic agent. Peritoneal surface area. Hydraulic conductance of the membrane. Reflection coefficient of the osmotic agent. Hydrostatic pressure gradient. Oncotic pressure gradient. Sieving. ULTRAFILTRATION

40. Transcapillary Ultrafiltration Transport of water across the capillary wall occurs through the small pore system and though aquaporin-1. Small pores =transport by hydrostatic & colloid osmotic pressure . Aquaporin-1 =dependent on the osmotic gradient. UFR=UFC( Δ P- Δ Π+Refl coeff . Δ O) Δ Π =colloid osmotic pressure gradient. Δ O= crystalloid osmolality gradient UFC is the product of the hydraulic conductivity and surface area and ranges from 0.04-0.08 mL /min in computer simulations

41. “Reflection coefficient” measures how effectively the osmotic agent diffuses out of the dialysis solution into peritoneal capillaires . Its value ranges from 0 to 1. Lower the value, faster the gradient is lost. Glucose has a RC of approx. 0.03 while icodextrin has a RC close to 1. Hydrostatic pressure of the capillaries is around 20mmHg, intraperitoneal pressure is around 7mmHg which exceeds 20mmHg while walking.

42. Differences in kinetics of glucose and icodextrin Glucose(1.5%) Icodextrin Peritoneal capillaries Hydrostatic pressure (gradient) 8 (9) 8 (9) 17 Colloid osmotic pressure (gradient) 0 (-21) 66 (45) 21 Osmolality 347, 486(4.25%) 285 305 Crystalloid osmotic pressure gradient. 24, 105(4.25%) -12 Net pressure gradient 12mmHg(93) 42mmHg

43. Differences in kinetics of glucose and icodextrin Thus from this 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 ”. In addition it tends to maintain the colloid oncotic gradient for a longer time as it is not absorbed due to it high reflection coefficient.

44. Application of physiology Fluid removal in clinical practice can be enhanced by Maximizing the osmotic gradient . Higher tonicity dwells. Shorter duration dwells ( eg . APD). Higher dwell volumes. Using osmotic agents with higher reflection coefficients ( eg . Icodextrin ). Increasing urine output ( eg . Duiretics )

45. Application of physiology Peritoneal Clearance of solute which is the net result of diffusion plus convective clearance minus the absorption can be increased by: Maximizing time on PD (no dry dwells). Maximizing concentration gradient. Frequent exchanges Larger dwell volumes Maximizing effective peritoneal surface area. Maximizing fluid removal.

46. Calculation of peritoneal clearance Peritoneal clearance is equal to the total daily dialysate volume multiplied by its solute concentration and divided by the plasma concentration of the solute. Peritoneal clearance(Kt)= 24hour dialysate volume XD/P Residual urine Kt is also calculated in the same way and added to peritoneal Kt. It is normalized to V to get the Kt/V. ( multiplty by 7 to get weekly Kt/V).

47. Peritoneal Equilibriation Test (PET)

48. Introduced by Twardowski et al. in 1987. It is a semiquantitative assessment of peritoneal membrane transport function in patients on peritoneal dialysis. The solute transport rates are assessed by the rates of their equilibration between the peritoneal capillary blood and dialysate .

49. Uses of PET Defining the baseline membrane characteristics of the patient to determine the best PD regimen. Assessment of inadequate dialysis and make necessary changes in regimen. Detecting Ultrafiltration Failure (UFF).

50. The standardized PET test An overnight 8 to 12 hour pre-exchange is performed. While the patient is in an upright position , the overnight exchange is drained (drain time not to exceed 25 minutes). Two liters of 2.5% dialysis solution are infused over 10 minutes with the patient in the supine position . The patient is rolled from side to side after every 400 mL infusion. After the completion of infusion (0 time) and at 120 minutes dwell time, 200 mL of dialysate is drained. A 10 mL sample is taken and the remaining 190 mL is infused back into the peritoneal cavity. During the four-hour dwell time, the patient is upright and allowed to freely ambulate.

51. A serum sample is obtained at 120 minutes . At the end of the dwell (240 minutes), the dialysate is drained in the upright position (drain time not to exceed 20 minutes). The drain volume is measured and a 10 mL sample is taken from the drain. All the samples are sent for solute measurement ( creatinine , urea, and glucose). The serum and dialysate creatinine concentrations are corrected for a high glucose level, which contributes to non- creatinine chromogens during the creatinine assay. The Dt /D0 glucose , and the D/P ratios for creatinine , urea, and others, are calculated.

52. Timing of PET First PET is done after 4-8 weeks of PD. If there is peritonitis, PET should be done 1 month after the resolution of peritonitis as there is a increased small solute transport and reduced UF during peritonitis. KDOQI does not recommend repeating PET. However, it may be useful to repeat the 4.25% modified PET annually to anticipate problems.

53. Transporter types High(Fast) transporters have Highest D/P ratios for Creat , Urea & Na Low net UF & D/Do values. Lower serum albumin values. Thus they do better with shorter dwells/APD Low(slow) transporters have Low D/P ratios for Creat , urea &Na. Good net UF and high D/Do values. Albumin losses are lower. They do better with longer dwells.

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