Peritoneal dialysis by Dr. Basil Tumaini

Peritoneal dialysis by Dr. Basil Tumaini, prepared for nephrology lecture during the residency in Internal medicine at Muhimbili University of Health and Allied Sciences

1. PERITONEAL DIALYSIS (PD) Dr. Basil Tumaini MD, MMED Resident 12 July 2017 Muhimbili University of Health and Allied Sciences

2. Introduction The dialysis modality of 11% of patients worldwide The proportion varies: < 5% in Japan > 60% in Mexico

3. Principle of PD Treatment

4. PERITONEAL DIALYSIS 1.5 – 3L of a dextrose-containing solution is infused into the peritoneal cavity and allowed to dwell for a set period, usually 2-4 hours Toxic material are removed through a combination of convective clearance generated through ultrafiltration and diffusive clearance down a concentration gradient

5. PD Rate of diffusion diminishes with time and eventually stops when equilibration between plasma and dialysate is reached

6. PD Absorption of solutes and water from the peritoneal cavity occurs across the peritoneal membrane into the peritoneal capillary circulation and via peritoneal lymphatics into the peritoneal lymphatic circulation The rate of solute transport may be altered by presence of infection (peritonitis), drugs and physical factors such as position and exercise

7. Abdominal cavity is lined by peritoneal membrane which acts as a semi-permeable membrane Diffusion of solutes (urea, creatinine, …) from blood into the dialysate contained in the abdominal cavity Removal of excess water (ultrafiltration) due to osmotic gradient generated by glucose in dialysate

8. The semi-permeable dialysis membrane of the peritoneum Comprises the capillary endothelium , supporting matrix and the peritoneal mesothelium Fluid and solutes move between the fluid-filled peritoneum and blood via what is termed, the ‘ three-pore model ’ of PD Large pores Small pores Ultrasmall pores

9. The semi-permeable dialysis membrane of the peritoneum … Large pores (20 – 40nm ): allow macro-molecules such as proteins , to be filtered between compartments (effectively via venular or lymphatic absorption) Small pores (4 – 6nm) : responsible for the transport of small solutes such as sodium, potassium, urea and creatinine Ultrasmall pores (<0.8nm) : transport water alone (shown to be aquaporin 1 )

10. The net movement of solutes, such as urea, will depend on Net diffusion through small pores and convection through large pores Total volume of dialysate infused Net fluid ultrafiltration (or, under certain circumstances, absorption)

11. Ultrafiltration (UF) The net movement of water relies on: P resence of a high intraperitoneal osmotic gradient (generated by glucose) or Presence of a high intraperitoneal oncotic gradient ( generated by glucose polymers, such as icodextrin )

12. Ultrafiltration (UF) … The osmotic gradient is usually generated by glucose and depends on: The glucose concentration of the dialysate A patient’s blood glucose The rate of absorption of glucose itself from PD fluid

13. Ultrafiltration (UF) … UF is optimized by: Ensuring normoglycaemia (relevant for diabetic patients ) Adjusting the tonicity of the PD solution (glucose concentration ) Altering the duration of each dialysis dwell. Adjusting dwell volumes ; ↑ volume often (but not always) leads to ↑ UF

14. DIALYSATE Primarily consists of water, osmotic agents (e.g. dextrose), electrolytes and minerals Preformed dialysis solutions are available typically ranging from 1.5 – 3L Lactate is the preferred buffer in peritoneal dialysis solutions, to control acidosis

15. DIALYSATE Most common additives: H eparin to prevent obstruction of dialysis catheter lumen with fibrin A ntibiotics to prevent infections. Insulin may be added in patients with diabetes mellitus

16. PERITONEAL DIALYSATE Peritoneal dialysate needs to remove uremic toxins normalize electrolytes correct acidosis remove fluid . Ideally fluid should be compatible with long-term peritoneal health

17. PERITONEAL DIALYSATE … Volume : usually 2L but 1.5, 2.5, or 3L also available Glucose concentration : three standard concentrations, usually about 1.5, 2.5 and 4.0% (roughly 25g, 50g, and 75g glucose per bag ) Sodium : Na + 135mmol/L (although lower concentrations may improve salt , and thus water, removal ) Other electrolytes : Ca 2 + ranges from 1.25 to 1.75mmol/L and 0.25mmol/L of Mg

18. PERITONEAL DIALYSATE … Buffer : bicarbonate is not compatible for storage with calcium and Mg in PD bags, so lactate (which is rapidly converted to bicarbonate in the liver) is widely used instead, at 35 – 40mmol/L e.g. in Dianeal ® Newer solutions may contain: Bicarbonate alone or in combination with lactate as buffer ( using bags mixed immediately pre-infusion ) Icodextrin (for an oncotic gradient), rather than glucose (as an osmotic gradient), to achieve UF Amino acids as nutritional supplement !

19. PERITONEAL DIALYSATE … Avoiding peritoneal glucose exposure High peritoneal glucose exposure over time (often years) predicts the development of UF failure, and causality has been suggested An alternative to glucose-containing dialysate is icodextrin ( Extraneal ®) Icodextrin is a 20-glucose polymer with potent colloidal effects (similar to albumin)

20. PERITONEAL DIALYSATE … Avoiding peritoneal glucose exposure … Icodextrin is particularly suited to high transporters It acts at the small intercellular pores and is only slowly lost from the peritoneal cavity , meaning that the oncotic gradient is maintained It therefore produces gradual and sustained UF over long dwell periods (overnight dwell in CAPD or daytime dwell in APD )

21. Biocompatible solutions PD fluid is sterilized through heat treatment During the process, at the pH of lactate-based glucose solutions, glucose degradation products (GDP ) and advanced glycation end-products (AGE) are formed These are believed to damage the peritoneal membrane leading to fibrosis

22. Biocompatible solutions Biocompatible solutions have been developed to ameliorate this and retrospective analysis of registry data suggested better patient survival Definitive evidence is lacking

23. ACCESS TO PERITONEAL CAVITY Obtained through peritoneal catheter (e.g., a Tenckhoff Catheter) Catheters used for maintenance peritoneal dialysis are flexible, being made of silicon rubber with numerous side holes at the distal end As with hemodialysis, optimal dose of peritoneal dialysis is unknown

24. Types of PD Catheters Overall PD catheter survival : +/- 90% at 1 year No particular catheter is superior

25. Placement of Peritoneal Dialysis Catheter

26. PD Catheter Exit Site

27. Peritoneal Dialysis (PD) PD Continuous Intermittent

28. Continuous PD Regimens Multiple sequential exchanges are performed during the day and night so that dialysis occurs 24 hours a day, 7 days a week CAPD: Continuous Ambulatory PD CCPD: Continuous Cyclic PD

29. FORMS OF PERITONEAL DIALYSIS Peritoneal dialysis may be carried out as: Continuous Ambulatory Peritoneal Dialysis (CAPD) Continuous Cyclic Peritoneal Dialysis (CCPD) or A combination of both

30. FORMS OF PERITONEAL DIALYSIS CAPD dialysis solution is manually infused into the peritoneum and exchanged 3 - 5 times daily APD/ NIPD/CCPD exchanges are performed in an automated fashion , usually at night. The patient is connected to an automated cycler

31. Forms of PD

32. CCPD Treatment Setup

33. FORMS OF PERITONEAL DIALYSIS

34. Intermittent PD Regimens PD is performed every day but only during certain hours DAPD: Daytime Ambulatory PD. Multiple manual exchanges during waking hours NPD: Nightly PD. Performed while patient asleep using an automated cycler machine. Sometimes, 1 or 2 day-time manual exchanges are added to enhance solute clearances

35. ILLUSTRATION

36. Advantages of PD Preservation of residual renal function. No need for vascular access. Mobility (e.g. easy to transport dialysis to holiday destinations). Patient engagement in treatment. Home-based therapy — maintains patient independence. Less expensive than HD. Less risk of transmission of blood-borne viruses.

37. Question 2 What is the most common cause of technique failure in peritoneal dialysis? (choose one answer): Ultrafiltration failure Malnutrition Peritonitis Non-adherence to the treatment regimen

38. COMPLICATIONS OF PD Peritonitis Catheter-associated non-peritonitis infections Catheter-associated noninfectious complications Metabolic disturbances Residual uremia

39. Peritonitis Usually occurs when there is break of aseptic technique during exchanges Defined as elevated peritoneal fluid leukocyte count (100/mm 3 , with at least 50% PMNs) Clinically there is fever, pain and cloudy dialysate Common culprits are gram-positive cocci Managed with intraperitoneal or oral antibiotics If gram-negative rods or yeast are involved, catheter removal is usually required

40. Risk factors T2DM , other significant comorbibity . Catheter type and implantation technique. Connection systems. Nasal carriage of Staphylococcus aureus .

41. Clinical features Abdominal pain, nausea, and vomiting ‘ Cloudy ’ PD effluent is very highly suggestive High fever, systemic sepsis with signs of an ileus, and peritonism may be present Patients should be taught to report cloudy effluent immediately A lways consider other causes of peritonitis (e.g. perforation, strangulated hernia, etc .)

42. Diagnosis PD fluid for microscopy and Gram stain : Preferably after dwell time of 4h > 100 WBC/mm 3 (>50% neutrophils ) Microscopy and culture of PD fluid (discuss with microbiology) and blood FBC ( ↑ WCC) and ↑ CRP Abdominal pain can be severe. Rapid peritoneal flushing can improve symptoms , but samples from the original cloudy bag should be sent for microbiology (and rapid flushing should be avoided once IP antibiotics have been administered )

43. Bacteriology Gram +ve cocci: 45 – 75% (coagulase-negative staphylococci, S. Aureus) often introduced after touch contamination of the connections or following catheter exit site infection Colonization of catheter biofilms can lead to recurrence of peritonitis and necessitate catheter exchange

44. Gram – ve organisms: 15 – 25% e.g., Pseudomonas , coliforms. Usually of bowel origin Air in the peritoneum is common and may not indicate bowel perforation Suspect perforation if mixed organisms on culture, and arrange appropriate imaging and/or exploration

45. Culture negative or ‘no growth’: ideally, cultures should be positive in >85% cases Higher yields may be obtained by inoculating blood culture bottles with PD fluid

46. Mycobacterial infections: 1% Consider in patients with culture-negative peritonitis not responding to empiric antibiotic therapy Smears of PD effluent are rarely positive for acid-fast bacilli, and diagnosis is usually made on culture (6-week) or at laparoscopy/ otomy , with confirmation on peritoneal biopsy.

47. Fungal: 3% Usually Candida spp. Peritonitis is infrequent but has a poor prognosis. It often follows antibiotic therapy in at-risk ( e.g.malnourished ) patients PD catheter removal is mandatory Allergic peritonitis e.g. to icodextrin may also occur

48. Management of peritonitis Initiate empiric antibiotics promptly GP : Vancomycin 2g IP on day 1, with a further dose on days 3 – 7, or a cephalosporin GN : cover with an aminoglycoside or third-generation cephalosporin IP administration is more effective than IV

49. Catheter-associated nonperitonitis infections Often termed tunnel infections Usually caused by S . aureus , Pseudomonas The use of prophylactic topical exit site ointment (e.g. mupirocin ) reduces such infections Can be managed with local antibiotic or silver nitrate administration M ay require parenteral antibiotics and catheter removal ( start flucloxacillin 500mg PO qid or ciprofloxacin 500mg PO bd for 14/7 if there is a history of Gram – ve infection)

50. Catheter-associated noninfectious complications O utflow failure Pericatheter leak Abdominal wall herniation Catheter cuff excursion and intestinal perforation

51. Metabolic Disturbances Hypoproteinemia from loss of albumin and other proteins obligates a high protein diet Hyperglycemia and weight gain due to absorption of several calories of dextrose and therefore can lead to other complications of insulin resistance Due to continuous removal of phosphorus and potassium, a more liberal diet is allowed

52. Residual uremia P articularly in patients with no residual kidney function

53. Switching from PD to HD There was a decline in PD utilization , threatening the viability of PD programs About 25% of PD patients switched to HD in 5-7 years, >70% of the switch occurring in the first 2 years Commonest causes of the switch were infections , fluid overload due to ultrafitration failure, abdominal surgery and malnutrition Jaar BG, Plantinga LC, Crews DC, Fink NE, Hebah N, Coresh J, Kliger AS, Powe NR. Timing, causes, predictors and prognosis of switching from peritoneal dialysis to hemodialysis : a prospective study . BMC nephrology. 2009 Feb 6;10(1):3.

54. PD adequacy: beyond calculation Absence of uremic symptoms Nutritional status, appetite, weight, serum albumin Fluid status Quality of life (e.g. by subjective global assessment scoring ) Improved biochemistry and correction of the complications of uraemia , such as anaemia

55. Switching from PD to HD … Independent predictors of the switch to HD included higher BMI and black race No significant difference on the survival between PD patients who switched to HD compared to those who remained on PD Jaar BG, Plantinga LC, Crews DC, Fink NE, Hebah N, Coresh J, Kliger AS, Powe NR. Timing, causes, predictors and prognosis of switching from peritoneal dialysis to hemodialysis : a prospective study . BMC nephrology. 2009 Feb 6;10(1):3.

56. WHICH MODALITY OT CHOOSE S election of which dialysis modality is driven by Patient’s choice M edical or social contraindication

57. Absolute contraindications to HD Thrombosed central veins Severe angina Hypotensive heart failure

58. Relative Contraindications to HD Long distance from HD unit Severe vascular disease Active diabetic retinopathy

59. Factors Influencing Dialysis Choice Dialysis Modality Contraindications Survival Quality of Life Treatment Satisfaction Other Factors: Late Referral, …

60. Absolute Contraindications for PD Colostomy , ileostomy, ileal conduit Abdominal wall infections or intra-abdominal sepsis, e.g., active diverticular disease Inguinal, umbilical or diaphragmatic hernias (esp. pleuroperitoneal leak) Intra-abdominal adhesions ?absolute vs relative Morbid obesity (inadequate clearance) ?absolute vs relative Very poor housing No spare space in home Poor personal hygiene

61. Relative Contraindications for PD Frailty/dementia ?absolute vs relative Huge polycystic kidneys ( insuffiecient intraperitoneal space) Severe gastroparesis (worsening vomiting) Severe lung disease (diaphragmatic splinting)

62. Absolute contraindications for PD Documented loss of peritoneal function or extensive abdominal adhesions (previous abd . Surgeries)  limit dialysate flow Uncorrectable mechanical defects (e.g., diaphragmatic hernia) In the absence of a suitable assistant, a patient who is physically or mentally incapable of performing PD. NKF K/DOQI Guidelines 2000

63. Peritoneal Adhesions

64. Factors Influencing Dialysis Choice Dialysis Modality Contraindications Survival Quality of Life Treatment Satisfaction Other Factors: Late Referral, …

65. Best Study Design to Compare Dialysis Modalities Prospective, randomized, clinical trial Significant barriers to performing this type of study 1 We are left with the analysis of observational data from well-conducted prospective studies 1 Korevaar JC et al. KI 2003; 64(6): 2222-2228

66. Quinn RR et al. 2011 (I) Country: Ontario, Canada Enrollment Years: 7-1-1998 to 3-31-2006 Follow-Up: 8 years Population Type: Incident – Elective Outpatient (databases @ Institute for Clinical Evaluative Sciences) Sample Size: HD: 4,538 PD: 2,035 Switching Modality: No Model(s) Intention-to-Treat (baseline modality) Quinn RR et al. J Am Soc Nephrol 2011; 22: 1534-1542

67. Several studies have suggested that the RR of death on PD as compared with HD increases over time This study showed that PD and HD are associated with similar survival in incident dialysis patients who have at least 4 months of predialysis care and start therapy electively as outpatients Quinn RR, Hux JE, Oliver MJ, Austin PC, Tonelli M, Laupacis A. Selection bias explains apparent differential mortality between dialysis modalities . Journal of the American Society of Nephrology. 2011 Aug 1;22(8):1534-42.

68. In contrast, when definitions of chronic dialysis that have been traditionally used to study the effect of dialysis modality on mortality were used, the RR of death on PD compared with HD increased over time, which is consistent with previous studies The association disappeared after excluding patients who started dialysis therapy urgently suggesting the apparent benefit to be due to bias Quinn RR, Hux JE, Oliver MJ, Austin PC, Tonelli M, Laupacis A. Selection bias explains apparent differential mortality between dialysis modalities . Journal of the American Society of Nephrology. 2011 Aug 1;22(8):1534-42.

69. Adjusted Survival between PD and HD, (received > 4 months of predialysis care and Started as outpatient) Quinn RR et al. J Am Soc Nephrol 2011; 22: 1534-1542 Adjusted HR: 0.96, p = 0.44

70. Biases Residual confounding: limited adjustment for known factors associated with mortality (e.g., comorbidities, lab data [albumin, …]) Short follow-up (1-2 years) in some studies Lead-time bias: baseline GFR Selection bias: patient characteristics Statistical Methodology: Center Effect: confounding by clinic as patient characteristics varied by center and treatment How to handle modality switching: As-Treated vs Intention-to-Treat No causal relationship, just association!

71. Other Issues: PD vs HD Beyond Survival In considering choice of dialysis technique, other issues must be considered …

72. Factors Influencing Dialysis Choice Dialysis Modality Contraindications Survival Quality of Life Treatment Satisfaction Other Factors: Cost of Care, Late Referral, …

73. Choices for Healthy Outcomes in Caring for ESRD ( CHOICE ) Study PD patients reported better QOL than HD patients in the following domains: Bodily pain Travel Diet restrictions Dialysis access Financial well-being Physical functioning (only at baseline, not at 1 year ) Wu AW, Fink NE, Marsh- Manzi JV, Meyer KB, Finkelstein FO, Chapman MM, Powe NR. Changes in quality of life during hemodialysis and peritoneal dialysis treatment: generic and disease specific measures . Journal of the American Society of Nephrology. 2004 Mar 1;15(3):743-53.

74. Choices for Healthy Outcomes in Caring for ESRD ( CHOICE ) Study At one year HD patients improved more on aspects of general health-related QOL than patients on PD HD patients had greater improvement on: Physical functioning Sexual functioning General health perceptions Wu AW, Fink NE, Marsh- Manzi JV, Meyer KB, Finkelstein FO, Chapman MM, Powe NR. Changes in quality of life during hemodialysis and peritoneal dialysis treatment: generic and disease specific measures . Journal of the American Society of Nephrology. 2004 Mar 1;15(3):743-53.

75. Factors Influencing Dialysis Choice Dialysis Modality Contraindications Survival Quality of Life Treatment Satisfaction Other Factors: Late Referral, …

76. CHOICE - Treatment Satisfaction: PD vs HD PD patients were significantly more likely to give excellent ratings of dialysis care overall compared to HD patients (85% vs 56%). Also PD patients were more likely to give excellent ratings for specific aspects of care: information on choosing a dialysis modality information on fluid removal staff and nephrologist availability coordination with other physicians caring of nurses or staff Rubin HR et al. JAMA 2004; 291: 697-703

77. Implications Each modality has distinct advantages or disadvantages Physicians should be as explicit as possible in describing specific tradeoffs and attempt to elicit individual preferences at start of dialysis Although there is no conclusive evidence that the choice of PD or HD provide a specific survival advantage: Better selection of PD patients (PD underutilized) PD patients should be monitored closely after the 2 nd or 3 rd year of dialysis Consider a “ timely ” transfer to HD (if or when PD problems arise)

78. What is the best long-term treatment? PD HD in-center HD home/ self-care Ask the nephrology providers which dialysis modality they would select if they had ESRD?

79. What is the best long-term treatment? Opinion vs Reality Ledebo I., Ronco C. NDT Plus 2008; 6:403-408 PD HD in-center HD home/ self-care

80. Question 3 Which one of the following patient ’ s characteristic or comorbidity is associated with better overall outcome on dialysis (choose one answer): Diabetes Mellitus + end-organ damage BMI > 30 Residual urine output of > 500 cc / day Colon cancer Early initiation of dialysis ( eGFR > 15)

81. Comparison of dialysis modalities

82. Is Timing of Dialysis Initiation Important in ESRD Patients? (Controversial)

83. IDEAL Study: K–M Curves for Time to the Initiation of Dialysis & for Time to Death Cooper BA et al. N Engl J Med 2010;363:609-619 Between July 2000 & November 2008 Australia / New Zealand 828 adults Early start: eGFR 10-14 cc/min Late start: eGFR 5-7 cc/min mean age 60.4 years 542 men & 286 women 355 with diabetes Median follow-up 3.6 years

84. Implications A total of 75.9% of the patients in the late-start group started dialysis when eGFR was > 7.0 cc/minute, owing to the development of symptoms! I n this study, planned early initiation of dialysis in patients with stage V CKD was not associated with an improvement in survival or clinical outcomes (QOL)  OK to delay initiation of dialysis ( eGFR < 7-10 cc/min)  D ialysis initiation should be based upon clinical factors (symptoms) rather than eGFR alone Cooper BA et al. N Engl J Med 2010;363:609-619

85. Why is Residual Renal Function Important in Dialysis Patients?

86. Why is baseline residual renal function important? Remaining GFR at start of dialysis make a significant contribution to the removal of potential uremic toxins Also facilitates regulation of fluid, electrolytes, and may enhance nutritional status and QOL Offers survival advantage in both HD and PD Suda T et al. Nephrol Dial Transplant 2000; 15: 396 Shemin D et al. Am J Kidney Dis 2001; 38: 85 Szeto C et al. Nephrol Dial Transplant 2003; 18: 977

87. Adjusted Hazard Ratio: 0.70 (0.52-0.93) p = 0.02 Shafi T., Jaar B., et al. Am J Kidney Dis. 2010;56:348-58 Cumulative Incidence of All-Cause Mortality in 579 HD Patients by Urine Status at 1 Year (CHOICE)

88. Implications Try to preserve r esidual r enal f unction in dialysis patients!  Less d ietary restriction  Better quality of life  Better survival Try to avoid n ephrotoxins if your dialysis patient still makes urine!

89. RRT other than HD and PD Kidney transplant

90. The Future …

91. Regenerative Medicine … Stem Cell Therapy … Wearable Artificial Kidney