1. Renal Replacement Therapy – What the Non-Nephrologist Should Know Bernard G. Jaar, MD, MPH, FASN,FNKF Johns Hopkins Medical Institutions Nephrology Center of Maryland

2. Why is this topic relevant to you?

3. Kidney Disease is a Public Health Problem Trends in Kidney Disease Burden …

4. Coresh, J. et al. JAMA 2007;298:2038-2047 Prevalence of CKD Stages in US Adults Aged 20 Years or Older: NHANES 1988-1994 and NHANES 1999-2004

5. ESRD Prevalence – The Forecast Projected growth overall ESRD prevalence (5% / yr) Gilbertson et al. JASN 2003 Number of patients (millions) Year 0.4 million 0.7 million 1.3 million 2.2 million (60% diabetic) 20002010202020301978 3.0 2.0 1.0 0 618,160 pts (2011)

6. Objectives Describe treatment options for renal replacement therapy Understand the general principles of dialysis modalities & compare their outcomes Importance of residual renal function Describe kidney transplantation process

7. Case Presentation (I) 39 y/o AA man PMHx: none Routine physical exam: –BP 142 / 100 –LE edema –4+ proteinuria (dipstick)

8. Case Presentation (II) PE: –Unremarkable, except: –Weight 230 lbs (BMI 33) –BP 138 / 85 –2+ LE edema Treatment: –ACE inhibitor –Thiazide diuretics Initial Nephrology Clinic Visit

9. Case Presentation (III) Labs: Albumin 2.5 T. cholesterol 398 mg/dL Serology w-u (-) UA:protein 4+, 0-2 RBC, 0-2 WBC Spot u. prot. / creat. 413 mg/dL / 41 mg/dL  10 Initial Laboratory Data 12.3 41.0 7490333 141 3.6 107 28 18 2.4 95 eGFR 37 cc/min/1.73m 2

10. CKD Progression  ESRD Initial presentation: HTN, CKD, proteinuria RRT Kidney Bx: FSGS “Uremic” ESRD

11. Indications for Renal Replacement Therapy Hyperkalemia Metabolic acidosis Fluid overload (recurrent CHF admissions) Uremic pericarditis (rub) Other non specific uremic symptoms: anorexia and nausea, impaired nutritional status, increased sleepiness, and decreased energy level, attentiveness, and cognitive tasking, …

12. What are the Treatment Options for Renal Replacement Therapy for our Patient?

13. ESRD Treatment Options ESRD Hemodialysis Kidney Transplant Peritoneal Dialysis Comfort Care

14. ESRD Treatment Options ESRD Hemodialysis Kidney Transplant Peritoneal Dialysis Comfort Care

15. Dialysis options Dialysis HemodialysisPeritoneal Dialysis In-Center HD (3 x week) Home HD (short daily, nocturnal) CAPD CCPD Home

16. Incident Patient Counts (USRDS) by 1 st Modality USRDS 2013 ADR

17. CKD Education

18. CKD Progression  ESRD Initial presentation: HTN, CKD, proteinuria RRT “Uremic” ESRD CKD Education

19.  Refer patients early, when eGFR < 30 cc/min  Education about types of renal replacement therapy: –Hemodialysis (vascular access +++) –Peritoneal Dialysis (QOL advantage +++) –Kidney Transplantation Refer when eGFR <20 Living kidney transplant (family, friends) Build time on list before dialysis initiation Even transplant before dialysis initiation (pre-emptive) CKD Education

20. Early Vaccination for Hepatitis B!  Patients with ESRD have  response to vaccination (2ary to general suppression of immune system)  After Hepatitis B vaccination in ESRD patients: –50 – 60 % develop antibodies, compared to > 90% in patients without renal failure –Have Lower titers –Have protective levels for shorter duration Stevens CE et al. NEJM 1984; 311: 496 Buti M et al. Am J Nephrol 1992; 112: 144 Too Often Forgotten !

21. Early Vaccination for Hepatitis B!  Patients with ESRD have  response to vaccination (2ary to general suppression of immune system)  After Hepatitis B vaccination in ESRD patients: –50 – 60 % develop antibodies, compared to > 90% in patients without renal failure –Have Lower titers –Have protective levels for shorter duration Stevens CE et al. NEJM 1984; 311: 496 Buti M et al. Am J Nephrol 1992; 112: 144

22. Hemodialysis (HD)

23. Principle of Hemodialysis Vein Artery

24. Hemodialysis Filter (Dialyzer)

26. Hemodialysis Vascular Access Polytetrafluoroethylene

27. Arteriovenous (AV) Fistula

28. Question 1 Which type of vascular access is associated with better outcomes in hemodialysis patients? (choose one answer): 1.Central venous cuffed catheter 2.Arteriovenous graft 3.Arteriovenous fistula 4.Temporary central venous catheter

29. Which Vascular Access and When Should It Be Placed?

30. CKD Progression Initial presentation: HTN, CKD, proteinuria HD Vascular Access (AVF)

31. Adjusted* Relative Risk of Death by Type of Vascular Access Diabetes No Diabetes Cohort: 5,507 patients, followed for 2 years *Adjusted for age, race, gender, BMI, history of smoking, PVD, CAD, CHF, neoplasm, ability to ambulate and education level. Prevalent diabetic pts: CVC vs. AVG (P = 0.42). Incident diabetic pts: CVC vs. AVG (P = 0.48). Prev. nondiabetic pts: CVC vs. AVG (P < 0.0001). Inc. nondiabetic pts: CVC vs. AVG (P = 0.82). Dhingra RK et al. Kidney Int 2001; 60: 1443–1451

32. Adjusted* Relative Risk of Death due to Infection by VA Type and Diabetes Status Cohort: 5,507 patients, followed for 2 years *Adjusted for age, race, gender, BMI, history of smoking, PVD, CAD, CHF, neoplasm, ability to ambulate and education level. Prevalent diabetic pts: CVC vs. AVG (P = 0.81) Prevalent nondiabetic pts: CVC vs. AVG (P < 0.13) Dhingra RK et al. Kidney Int 2001; 60: 1443–1451

33. Astor B. et al. Am J Kidney Dis 2001; 38 (3): 494-501 Patients who started using an AV access by timing of first referral to a nephrologist N=356 hemodialysis patients

34. VASCULAR ACCESS GUIDELINES  Arm veins suitable for placement of vascular access should be preserved, regardless of arm dominance. Arm veins, particularly the cephalic veins of the non- dominant arm should not be used.  Dorsum of the hand could be used for IV.  A Medic Alert bracelet should be worn to inform hospital staff to avoid IV cannulation of essential veins.  Subclavian vein catheterization should be avoided for temporary access in all patients with CKD (  stenosis  preclude use of ipsilateral arm for vascular access)

35. SAVE the Non-Dominant ARM for Vascular Access  When GFR < 30 mL/min –No BP measurement –No IV –No Blood Draws  Place vascular access within a year of hemodialysis anticipation … On Non-Dominant Arm

36. Peritoneal Dialysis (PD)

37. Principle of PD Treatment

38. 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

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

40. Placement of Peritoneal Dialysis Catheter

41. Placement of PD Catheter Exit Site

42. PD Catheter Exit Site

43. Peritoneal Dialysis (PD) PD ContinuousIntermittent

44. 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

45. 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

46. CCPD Treatment Setup

47. Question 2 What is the most common cause of technique failure in peritoneal dialysis? (choose one answer): 1.Ultrafiltration failure 2.Malnutrition 3.Peritonitis 4.Non-adherence to the treatment regimen

48. Cumulative percentage of PD patients by time from 1 st dialysis to 1 st switch to HD Jaar BG et al. BMC Nephrol 2009; 10: 3 25% of PD patients switched to HD within 5-7 years

49. Causes of PD Technique Failure (Switching from PD to HD) Peritonitis Ultrafiltration Failure Malnutrition Abdominal Surgery Psychological Issues Jaar BG et al. BMC Nephrol 2009; 10: 3

50. Which Dialysis Modality Provides the Best Outcomes?

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

52. 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

53. Peritoneal Adhesions

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

55. 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

56. 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

57. 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

58. 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!

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

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

61. CHOICE - Quality of Life: PD vs HD (I) PD patients reported better QOL then 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 A et al. JASN 2004; 15: 743-753

62. 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 A et al. JASN 2004; 15: 743-753 CHOICE - Quality of Life: PD vs HD (II)

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

64. 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

65. 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)

66. What is the best long-term treatment? 1.PD 2.HD in-center 3.HD home/ self-care Ask the nephrology providers which dialysis modality they would select if they had ESRD?

67. What is the best long-term treatment? Opinion vs Reality Ledebo I., Ronco C. NDT Plus 2008; 6:403-408 1.PD 2.HD in-center 3.HD home/ self-care

68. Question 3 Which one of the following patient’s characteristic or comorbidity is associated with better overall outcome on dialysis (choose one answer): 1.Diabetes Mellitus + end-organ damage 2.BMI > 30 3.Residual urine output of > 500 cc / day 4.Colon cancer 5.Early initiation of dialysis (eGFR > 15)

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

71. 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

72. 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! In 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)  Dialysis initiation should be based upon clinical factors (symptoms) rather than eGFR alone Cooper BA et al. N Engl J Med 2010;363:609-619

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

74. 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

75. 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)

76. Implications Try to preserve residual renal function in dialysis patients!  Less dietary restriction  Better quality of life  Better survival Try to avoid nephrotoxins if your dialysis patient still makes urine!

77. Kidney Transplantation

78. Principle of Kidney Transplantation Iliac Fossa

79. Question 4 Which one of the following statements is correct? (choose one answer): 1.CKD patients can be referred to a transplant center when their GFR is < 20 cc/min/1.73m 2 2.Pre-emptive and live kidney transplants are associated with better graft survival 3.Most common cause of kidney transplant loss is death with a functional transplant 4.All of the above

80. Trends in Transplantation: patients age 20 years & older USRDS ADR 2012

81. Adjusted Relative Risk of Death among 23,275 Recipients of a 1st Cadaveric Transplant Wolfe RA et al. N Engl J Med 1999;341:1725-1730

82. Mange K et al. N Engl J Med 2001;344:726-731 K-M Estimates of Allograft Survival According to the Use or Nonuse of Long-Term Dialysis before Kidney Transplantation from a Living Donor Adjusted Rate Ratio (95% CI): 0.16 (0.07–0.35) P = 0.009

83. Acute Rejection within the 1 st Year Post-Transplant Patients age 18 & older with a functioning graft at discharge. USRDS ADR 2012

84. Cumulative incidence of post-transplant diabetes Patients receiving a first-time, kidney-only transplant, 2003–2007 combined. USRDS ADR 2012

85. Causes of Death in Kidney Transplant Patients with Functioning Graft 2006–2010 First-time, kidney-only transplant recipients, age 18 & older, 2006– 2010, who died with functioning graft. USRDS ADR 2012

86. Posttransplant Malignancy Risk is 4X to 100X compared rates of malignancy in the general population No comprehensive reporting system Available data suggesting 2- to 3-fold under- reporting The precise rate is UNKNOWN Accounts for 10% of deaths in kidney recipients with functioning graft  SCREENING is KEY!

87. Immunization for Kidney Transplant Recipients Recommended  Influenza types A and B (yearly)  Pneumovax (every 3-5 years)  Diphteria-Pertussis- Tetanus  Haemophilus influenza B  Hepatitis A and B  Inactivated polio  Meningococcus Not Recommended  Varicella zoster  Intranasal influenza  BCG  Live oral typhoid  Measles, Mumps, Rubella  Oral polio  Yellow fever  Smallpox  Live Japanese B encephalitis vaccine

88. Key Concepts (I) Kidney transplantation is the most cost- effective modality of renal replacement Transplanted patients have a longer life and better quality of life Early transplantation (before [pre-emptive] or within 1 year of dialysis initiation) yields the best results Living donor kidney outcomes are superior to deceased donor kidney outcomes

89. Key Concepts (2) Early transplantation is more likely to occur in patients that are referred early to nephrologists Refer for transplant evaluation when eGFR < 20 cc/min/1.73m 2 Success of transplantation results from a delicate balance between the suppression of the immune system to prevent rejection and the long-term side-effects of immunosuppression

90. Key Concepts (3) The most common cause of transplant loss is death with a functional transplant due to –Heart disease +++ –Infections –Malignancies Immunosuppressants are essential to prevent immunological loss of the transplant but side effects can also lead to transplant loss

91. What are the Costs of the Different Renal Replacement Therapy Modalities?

92. Costs (in Billion) of Medicare and ESRD Programs in 2010 488,938 ESRD patients representing less than 1% Medicare population USRDS ADR 2012 ESRD Cost $32.9 (6.3%) Total Medicare Costs $522.8

93. Total Medicare ESRD expenditures per person per year, by modality USRDS ADR 2012 Period prevalent ESRD patients Patients with Medicare as secondary payor are excluded $87,561 $66,751 $32,914

94. What About No Renal Replacement Therapy Option?

95. Starting Dialysis in the Elderly…Or Not? Among patients > 75 yrs with stage 5 CKD who chose NOT to start dialysis: –Overall, more likely to die over next 1-2 years –But if they had ischemic heart disease or other significant comorbidity  NO DIFFERENCE in survival Active disease management and supportive care may be appropriate without starting dialysis in the ill elderly Must have end-of-life discussions! Murtagh, et al. Nephrol Dial Transplant. 2007; 22(7): 1955-1962

96. The Future …

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

98. Thank You ! QUESTIONS?