1. The New Dialysis Patient Lawrence Kleinman, MD Lawrence Kleinman, MD ANNA Spring Conference Chateau Briand, Carle Place, NY May 23,2012 May 23,2012

2. Resources Hemodialysis http://www.nejm.org/doi/abs/10.1056/NEJMra0902710http://www.nejm.org/doi/abs/10.1056/NEJMra0902710 J. Himmelfarb and T. A. Ikizler| November 4, 2010 | N Engl J Med 363:1833 A Randomized, Controlled Trial of Early versus Late Initiation of Dialysis http://www.nejm.org/doi/abs/10.1056/NEJMoa1000552 http://www.nejm.org/doi/abs/10.1056/NEJMoa1000552 B. A. Cooper and Others| August 12, 2010 | N Engl J Med 363:609 CME The Initiation of Renal-Replacement Therapy — Just-in-Time Delivery http://www.nejm.org/doi/abs/10.1056/NEJMe1006669 N. Lameire and W. V. Biesen| August 12, 2010 | N Engl J Med 363:678 ASN Renal Weekends 2011 Long Interdialytic Interval and Mortality among Patients Receiving Hemodialysis http://www.nejm.org/doi/abs/10.1056/NEJMoa1103313http://www.nejm.org/doi/abs/10.1056/NEJMoa1103313 R. N. Foley and Others| September 22, 2011 | N Engl J Med 365:1099

3. “THE STANDARD” Fistula Kt/V EPO – Hgb ? - 11 B/P control with meds Sodium modeling Early Start Everyone Start Routine Treatment

4. Original Article A Randomized, Controlled Trial of Early versus Late Initiation of Dialysis Bruce A. Cooper, M.B., B.S., Ph.D., Pauline Branley, B.Med., Ph.D., Liliana Bulfone, B.Pharm., M.B.A., John F. Collins, M.B., Ch.B., Jonathan C. Craig, M.B., Ch.B., Ph.D., Margaret B. Fraenkel, B.M., B.S., Ph.D., Anthony Harris, M.A., M.Sc., David W. Johnson, M.B., B.S., Ph.D., Joan Kesselhut, Jing Jing Li, B.Pharm., B.Com., Grant Luxton, M.B., B.S., Andrew Pilmore, B.Sc., David J. Tiller, M.B., B.S., David C. Harris, M.B., B.S., M.D., Carol A. Pollock, M.B., B.S., Ph.D., for the IDEAL Study New England J Med Volume 363(7):609-619 August 12, 2010 In this study, adults with progressive chronic kidney disease and an estimated glomerular filtration rate between 10 and 15 ml per minute per 1.73 m2 (stage V chronic kidney disease) were randomly assigned to early or late initiation of dialysis. Early initiation of dialysis was not associated with an improvement in survival or clinical outcomes.

5. Enrolment, Randomization, and Follow-up Cooper BA et al. N Engl J Med 2010;363:609-619

6. Timing at the Start of Dialysis 25,901 incident adult HD patients from the Canadian Organ Replacement Register (CORR) 100 90 80 70 60 50 40 30 20 10 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Clark et al, CMAJ, 2010 Avg 7ml/min Avg 15ml/min P < 0.05 Time from dialysis start

7. Survival by age at start of dialysis across DOPPS regions. Canaud B et al. CJASN 2011;6:1651-1662 ©2011 by American Society of Nephrology

8. Arteriovenous Fistula  National sample: FMC database all incident patients (2007)  AVF:AVG=3:1 ratio (6365:1916) *fistula’s placed earlier than grafts *patients with AVG are older, female, black, with diabetes  Mature AVG- median time to failure 119 days  Mature AVF –median time to failure 87 days  Catheters removed from :71% of mature grafts  59% of mature fistulas  AVG matured twice as fast than AVF (49 days vs 119 days) Note: Surgical quality of access need to be examined more closely. Delays in access maturation requires prompt attention.

10. Kaplan–Meier Curves for the Time to Catheter Malfunction, According to Study Group. Hemmelgarn BR et al. N Engl J Med 2011;364:303-312.

11. ADEQUACY IF ANY MAJOR ORGAN WERE TO BE “SHUT DOWN” & REPLACED WITH INTERMITTENT FUNCTION, WOULD THAT EVER BE “ADEQUATE”? Think beyond Kt/V One size DOES NOT fit all!

12. TIME Important in terms of adequacy – “the driving” component of Kt/V Equally, if not, MORE important in terms of volume control Ultrafiltration rate: amount of UF/time The higher the UF rate, the higher the associated mortality rate!

13. Summary of Observational Studies comparing outcomes associated with short and long term hemodialysis treatment time Clinical Journal of the American Society of Nephrology

14. Modifiable treatment Practices and sudden death

15. Association of longer treatment time with lower mortality and hospitalizations Patient model All-cause mortality Cardiovascular death Sudden death Any hospitalization Hospitalization due to CHF Or fluid overload Facility model 0.80 0.90 1.00 1.10 0.80 0.90 1.00 1.1 HR per 30 minutes longer (95% Cl) N=37,414 patients from DOPPS 1-3

16. Non-traditional Risk factors unknown Traditional risk factors Pump Abnormalities Left Ventricular hypertrophy (LVH) Cardiovascular Disease Cerebrovascular disease Peripheral Vascular Disease Conduction Abnormalities Coronary Heart Disease Pathogenesis of LVH

17. LVH Central Role in Dialysis Care LVH progresse with severity and duration of CKD But: 10% reduction in LVMI in ESRD is associated with: *22% in all causes *28% in CV mortality LVH CKD/ESRD ECFV Other factors SBP Cardiac Fibrosis  Sudden cardiac death  dilated cardiomyopathy and CHF  Ischemic heart disease  stroke 4d trial-Krane Vet.al CJASN,2009 London GM, et al JASN,2001

18. The predominant cause of LVH is not poor medical control of hypertension,but poorly managed extra-cellular volume expansion Our concept of dry weight is killing more patients than al of the angst about kt/v,pth,hgb,p,lipids…..

19. The serious Inter and Intra-dialytic Impact of Excess ECVF + Sodium HTN LVH CV Events MORTALITY THE IMPORTANCE OF DRY WEIGHT AND HOW TO MEASURE IT Volume Overload Agarwal R,Et’al Am J Med 2003

20. Impact of Fluid Overload on survival Wiseman nephrol Dial Transplant,2009 Variable Hazard Ratio P value Age (1 year)1.06<0.001 Dialysis vintage (1/year) 0.9990.052 Diabetes (y/n) 1.60.03 IDWG0.90.5 Fluid overload (<2,5L) 2.60.002 265 patients;7year follow up; all cause mortality Fluid overload of>2,5 l is linked to a dramatic HR 1.0 0.6 0.4 0.2 0.0 10080604020 0 Time (months) survival 0.8 FO>2.5 L FO<2.5 L

21. What BP Target Use home BP measures to guide tx goal BP -home systolic BP linked to mortality -Best home SBP 120-130 mmHg -Best ambulatory systolic is 110-120mm Hg  Use dialysis unit BP measure to guide tx prescription  Individualize according to co-morbidity

22. Blood Pressure and Salt in Hemodialysis Conclusions: Require reductions in both dietary & intradialytic Na+ influx to: Lead to reduction in IDWG Improve intradialytic hemodynamic stability Reduce antihypertensive medication burden

23. BP Control Volume Control BP control  Get dry weight  Add oral furosemide  Rigorous NaCl control in the interdialytic interval;  Eliminate Na+modeling; lowering Dialysate Na+ RAS control  Add low dose ACE/ARB  Consider prophylactic carvedilol

24. ESTIMATED DRY WEIGHT reflects patient’s ability to tolerate a given amount of Ultrafiltration over a given amount of time. considered as a way of managing HTN and reducing anti-hypertensive medications Clear lungs and lack of edema NOT indicative of achieving EDW Alternative methods for improving accuracy – ex:Hematocrit lines, Bioimpendance

25. Impact of Ultrafiltration Rate Post-hoc analysis HEMO Study data (N=1,846) UFR considered at baseline Outcomess: all cause and CV mortality Risks of all-cause and CV- related mortality begin to increase at rates >10ml/h/kg 2.5 Mortality All CV Associations between UFR and CV and all-cause mortality Flythe, et al. Kidney Int; 79:250-257;2011 CV mortality All-cause mortality UFR (ml/hr/kg) 5 10 15 20 1 1.2 1.4 1.6 1.8 2 Adjusted hazard ratio 70 kg patient with 3K IDWG 4 h 3 h

26. SODIUM Ideally, dialysate sodium should be slightly lower, than the patient’s sodium level Currently, sodium is viewed more as a way to stabilize intra-dialytic blood pressure rather than a way to “ultrafiltrate” and reduce circulating volume Traditional “sodium modeling” results in a gain of sodium, an increase in post-dialytic thirst, resulting in increased interdialytic wt gain

27. TEMPERATURE Normal dialysate temperature (37° C) results in positive thermal gain, resulting in vasodilation and drop in B/P Lower temperature dialysate prevents the thermal gain and results in greater stability of B/P Lowering dialysate temperature should be one of the first considerations in improving intra-dialytic stability

28. ANEMIA EPO Iron Loss – at the LEAST – significant iron losses 3x/wk (HD) Iron absorption - impaired in ESRD due to inflammation/hepcidin Best mix of EPO + Iron is NOT KNOWN In fact, despite processes that suggest 10-11 is the “appropriate” target, the truth is that WE DON’T KNOW!

29. CALCIUM, PHOSPHOROUS, & PTH Contribute to Cardiovascular disease The higher the phosphorous, the higher the chances of the lining of blood vessels turning into bone The higher the Ca x Phos value, the greater calcification of heart valves Calcified heart valves are a potential environment for endocarditis Consider using a low Calcium dialysate

30. Original Article Long Interdialytic Interval and Mortality among Patients Receiving Hemodialysis Robert N. Foley, M.B., David T. Gilbertson, Ph.D., Thomas Murray, M.S., and Allan J. Collins, M.D Patients receiving thrice-weekly hemodialysis have two 1-day intervals and one 2-day interval between treatments. This study shows that the risks of death and cardiovascular events leading to hospital admission are increased during the long (2-day) interdialytic interval. N Engl J Med Volume 365(12):1099-1107 September 22, 2011

31. Admission Rates and Mortality on Different Days of the Week

32. Kaplan–Meier Curves for the Primary End Point in the Two Study Groups. Fellström BC et al. N Engl J Med 2009;360:1395-1407.