1. Residual Renal Function (RRF)
Thomas A. Golper, MD, FACP, FASN presiding
Program Schedule
• 4:45 to 5:05--- Should volume overloaded dialysis patients
be aggressively ultrafiltered to “dry weight” even if RRF
declines?
– Thomas Golper
• 5:05 to 5:25--- Residual kidney function is a vital tool to
improve outcomes
– Bernard Canaud
• 5:25 to 5:45--- How can we preserve RRF on dialysis?
– Isaac Teitelbaum
• 5:45 to 6:00 ---Discussion

2. Should volume overloaded dialysis
patients be aggressively ultrafiltered
to “dry weight” even if RRF declines?
Thomas A. Golper, MD, FACP, FASN
Vanderbilt University Medical Center
Nashville, TN
thomas.golper@vanderbilt.edu
Potential Conflict of Interest Disclosure
Consultant: Baxter Healthcare,
Honoraria: Baxter, Fresenius North America, Genzyme

3. Consequences of Volume Overload
Volume Overload
Hypertension
↑ Pre-Load ↑ After-Load Inflammation
↓ RRF
Left Ventricular Hypertrophy
and abnormal remodeling Atherosclerosis
Congestive Heart Failure
↑ Cardiovascular Morbidity and
Mortality
Courtesy of Dr Raj Mehrotra

4. Should volume overloaded dialysis
patients be aggressively ultrafiltered
to “dry weight” even if RRF declines?
No
Thomas A. Golper, MD, FACP, FASN
Vanderbilt University Medical Center
Nashville, TN
thomas.golper@vanderbilt.edu
Potential Conflict of Interest Disclosure
Consultant: Baxter Healthcare,
Honoraria: Baxter, Fresenius North America, Genzyme

5. Hold it right there.
Doesn’t excess volume kill?

6. Hold it right there.
Doesn’t excess volume kill?
It sure does.

7. NT-Pro-Brain Naturetic Peptide
Levels Predict Survival in PD
Paniugua et al CJASN 3:407, 2008
ADEMEX trial baseline levels prior to randomization; independent of
dialysis intensity

8. NT-Pro-Brain Naturetic Peptide and
CV Outcomes in PD Patients
Wang et al, JASN 18: 321, 2007
230 prevalent PD patients, followed for 3 years

9. B-Type Naturetic Peptide In HD Pts
Koch et al Clin Nephrol 73:21, 2010
• Background
– Plasma levels of hormone released predominantly by
LV myocytes as result of pressure or volume loading
(stretch)
– Plasma levels not influenced by renal dysfunction
• Tagore et al CJASN 3:1644, 2008
• Prospective Observations 255 Dialysis Patients, stratified
by < 340 pg/mL vs. > 340 pg/mL
• Higher BNP at baseline was associated with shortened
survival
• The co-morbidity severe CHF over rides BNP
• In absence of severe CHF, BNP is predictive

10. Hold it right there.
Doesn’t excess volume kill?
It sure does.
But it doesn’t have to.

11. Trade Off
Volume Excess vs. Loss of RRF
• Very few patients have malignant hypertension
from mild volume overload
• Very few incident dialysis patients initiate for
pulmonary edema or malignant hypertension
• Gentle initiation or incremental dialysis is feasible
in most initiates

12. What we know about RRF

13. RRF Better Preserved in PD vs. HD
• Rottembourg, 1982. 25 pts on each followed for 18
months with GFR going from 4.4 to 4.0 in CAPD
and from 4.3 to 1.3 in HD (p < 0.01). Updated in
1993 with more diabetics, same result.
• Cancarini et al, 1986. The PD pts slower decline of
RRF but not for all diagnoses.
• Feber, 1994. Children on PD preserve urine output
better on PD, but GFR not preserved.
• Park, 2000. PD pts having HD treatments for a
month lost GFR faster than PD pts not needing HD
(confirmed X 1)

14. RRF Better Preserved in PD vs. HD
Lysaght MJ, et al, ASAIO Trans 37:598, 1996
6
N = 57
5
RRF Cr Cl (mL/min)
The difference persists after adjustment for age,
4
N = 58 sex, hypertensive status and the use of ACEI
HD
3
PD
2
1
0
0 6 12 18 24 30 36 42 48
Months on dialysis

15. RRF Better Preserved in PD vs. HD
Moist et al. JASN 11:556, 2000
Wave 2 DMMS of USRDS 811 HD pts and 1032 PD pts
PD pts had a 65% lower risk of losing RRF compared to HD pts
At each time interval, HD pts were 3X more likely to have lost RRF
Adjusted Odds Ratios
1
0.8
*
0.6
p = 0.001
0.4 p = 0.0001
0.2
0
PD Univariate PD Multivariate HD
. Analysis Analysts

16. Patient Survival Probability for Patients Initiating
Dialysis with PD Compared to HD (1990-94)
Fenton et al, AJKD 30:334, 1997
100
CAPD/CCPD
90
HD
80
Probability (%)
70
60 Period of
50 Preserved RRF on PD
40
30
0 6 12 18 24 30 36 42 48 54
Follow-up months

17. Patient Survival Probability for Patients Initiating
Dialysis with PD Compared to HD (1990-94)
Fenton et al, AJKD 30:334, 1997
100
CAPD/CCPD
90
HD
80
Probability (%)
70
60 Period of
50 Preserved RRF on PD
40
30
0 6 12 18 24 30 36 42 48 54
Follow-up months
Not controversial as similar findings confirmed
in numerous other data sets

18. Does PD Slow the Rate of RRF Loss?
Ramon et al PDI 22:239, 2002
• 14/36 PD pts had Q 1-2 month
Cr Cl studies for > 12 months
prior to PD and started this
p < 0.0005
period with Cr Cl > 20, then
followed on PD for > 6
months
• Mean rate of loss of RRF was
less on PD for all pts
• Consistent with at least two
rat model studies

19. Why Would This Be?
• Volume overload at initiation portends a poor outcome
• Is this a condemnation of predialysis care?
– The damage is already done so the patient’s goose is
cooked no matter what happens next
• Is this a condemnation of post dialysis care?
– The patient was left volume overloaded
• Is it merely identifying multi-organ failure?

20. Extracellular Volume
PD vs. HD
Plum et al NDT 16:2378, 2001
PD pts are overloaded

21. Compared To HD Patients
PD Patients……
• Are more frequently in volume excess
• Have better early survival
• Have better preservation of RRF

22. Benefits of RRF In Dialysis Patients
Dr. Canaud’s talk is next
• Better BP control
– Menon et al NDT 16:2207, 2001
– Ates et al KI 60:767, 2001
• Higher liklihood of euvolemia
– Konings et al NDT 18:797
• Normalization of LVMI
– Wang et al KI 62:639, 2002
• Survival
– Diaz Buxo et al AJKD 33:523, 1999
– Rocco et al KI 58:446, 2000
– Bargman et al JASN 12:2158, 2001

23. The conundrum continues
because volume excess is bad for
our patients

24. PD

25. Na/Fluid Removal and Mortality in PD Pts
EAPOS- Brown et al JASN 14:2948, 2003
• Failure to achieve > 750 mL/day of UF in anurics, and
• Regardless of RRF, Na and fluid removal predict survival
NECOSAD Jansen et al KI 68:1199, 2005
• In anuric PD pts each L/day of UF reduces RR of death by 52%
Ates et al., KI 60:767, 2001
• 125 incident PD patients, 3-year follow up
• Cox multivariate predictors of mortality in addition to hypertension
and comorbidity score:
Parameter RR p
– RRF 1 mL/min 0.53 <0.05
– Na removal (10 mEq/d) 0.90 <0.001
– Total Fluid removal 0.90 <0.01
(100 ml/d)

26. Increased Peritoneal UF Is Associated
With Lower BP
Tonbul et al PDI 23:46-52,2003
• Baseline:
– 25 PD patients, Mean time on PD 22.9 mo’s, 13/25 HTN
– All patients on same regimen 3 x 1.5% & 1 x 4.25%
– Attempt to increase UF with F/U at 1 month
– 13/25 had HTN (BP>180/110) and an increase in RX
• Results:
– UF increased (1086+259 to 1493+225 mL, p<0.001)
– Systolic BP (145+13 vs. 128+5 mmHg)
– Diastolic BP (96+10 vs. 81+3 mmHg, p<0.001)
– Weight decreased (67.3+8.9 to 65.5+8.7 Kg)
– BP meds discontinued in 6/13

27. Strict Volume Control Normalizes
BP, But At What Price?
Gunal et al AJKD 37:588, 2001
• Aggressive dietary approach, followed by UF
approach, lowered the body wt 2.8 kg in 47
hypertensive PD pts
• BP 158/96 dropped to 120/78
• CTI decreased
• In 19 pts with RRF, daily urine volume dropped to
28% of pre-treatment
• Kt/V dropped from 2.06 to 1.85 with loss of RRF
What is the perfect balance?

28. Does Improved Fluid Status
Hurt RRF?
Davies et al JASN 14:2338, 2003
• Double blind randomized controlled trial of
icodextrin vs. 2.5% dextrose for long dwell
• Icodextrin group lost weight, total body water and
salt, dextrose group gained all three (p< 0.05)
• BP control not different
• Urine volume better maintained in icodextrin
group
– 89 mL/d (p <0.04)

29. High BP and Survival on PD
Just How Bad Is It?
• Jager et al KI 55:1476, 1999
– NECOSAD Prospective observational muti-
center cohort study of 118 consecutive incident
PD pts
• RR of death of 1.42 for each 10 mmHg BP
• Merkus AJKD35:69, 2000
– Post Hoc analysis
– 8.6 greater risk if MAP > 107 than if less
• Goldfarb-Rumyantzev et al NDT 20:1693, 2005
– Wave 2 DMMS showed that only a very low
BP was associated with high death risk

30. HD
Hypertension and volume excess in
hemodialysis:
how aggressive should we be and at
what price?

31. Higher Mortality With Larger
Interdialytic Weight Gains
Kalantar-Zedah et al Circulation 119:671,2009
• DaVita data base 2001-2003
• 34,000 pts divided into 8 categories of 0.5 kg
increments in interdialytic wt gains, each
treatment, each 3 months an average determined
• 1.5 -2.0 kg wt gain = reference
• < 1.5 kg gain hazard ratio 0.67
• > 4.0 kg gain hazard ratio 1.25
• Across all subgroups

32. Higher Mortality With Larger
Interdialytic Weight Gains
Kalantar-Zedah et al Circulation 119:671,2009
• DaVita data base 2001-2003
• 34,000 pts divided into 8 categories of 0.5 kg
increments in interdialytic wt gains, each
treatment, each 3 months an average determined
• 1.5 -2.0 kg wt gain = reference
• < 1.5 kg gain hazard ratio 0.67
• > 4.0 kg gain hazard ratio 1.25
• Across all subgroups
We presume that volume mediates its mortality effects
by hypertension and progressive heart failure

33. Observational Data Describing BP
And Mortality In HD
Luther and Golper
KI 73:667, 2008
Counterintuitive
Reverse epidemiology
U or J
shaped

34. Reverse Epidemiology:
Risk Factor Paradox In The Chronically Ill
Possible Causes
• Survival bias:
– Only a small fraction of CKD pts survive to get to
ESRD
– Survival of the most fit!
• Competitive risks have different influences over time
– e.g. malnutrition will get you sooner than overnutrition
• Presence of the malnutrition-inflammatory complex
reverses the risk factors itself

35. Relationship Between BP and
Mortality Changes Over Time
Stidley et al JASN 17:513, 2006
• DCI database, 17,000 incident HD pts, 1993-2003
• Covariates: gender, age, race, cause of ESRD, Kt/V,
albumin, Hct, antihypertensive drug use or not in first 90
days
• Modeled baseline BP (days 31 to 120) and mortality, and
then time-varying BP and time-varying covariates
• Median pt f/u was 2.05 yrs, slightly more blacks in DCI set
than USRDS, but otherwise similar

36. Stidley et al JASN 17:513, 2006

37. Stidley et al JASN 17:513, 2006
Early years

38. Stidley et al JASN 17:513, 2006
Early years
Later years

39. Relationship Between BP and
Mortality Changes Over Time
Stidley et al JASN 17:513, 2006
• Relationship between baseline BP and mortality changes
over time
– Low SBP increases mortality in early yrs (<2)
– Adverse effects of high SBP are later (>3) and not large
• DBP hazard in HD similar to general population
• Ideal BP in HD pts not yet identified
• High SBP post HD is more of a predictor for mortality than
is predialysis SBP
– Raises issue of intradialytic hypertension

40. So now maybe we should treat
hypertension more aggressively in
HD patients

41. Achieving BP Targets in HD
Davenport et al KI 73:759, 2008
• Audit of BP control using RA GLs of 2002, 11 London
Units, over one week, 2600 pts, almost 8000 dialysis
sessions
• 36% of pts achieved predialysis BP < 140/90
• 42% of pts achieved post dialysis BP < 130/80
• 15% of pts had enough symtomatic intradialytic
hypotension to require fluid resuscitation
– Failure to achieve dry wt not counted
– 7% of all dialysis sessions
• Intradialytic hypotension more prevalent in centers
achieving lower post dialysis BP

42. Complications of Aggressive BP Control
Davenport et al KI 73:759, 2008
30
% patients in dialysis centre with
intradialytic hypotension
25
r = 0.8, p = 0.003
20
15
10
5
0
0 10 20 30 40 50 60
% of patients in dialysis centre achieving post dialysis blood pressure target

43. Complications of Aggressive BP Control
Davenport et al KI 73:759, 2008
30
% patients in dialysis centre with
More frequent
hypotension as
intradialytic hypotension
25
a consequence
r = 0.8, p = 0.003 of aggressive
20
targets
15
10
5
0
0 10 20 30 40 50 60
% of patients in dialysis centre achieving post dialysis blood pressure target

44. Improved Volume Status Is
Associated with Improved Nutrition
Cheng et al AJKD 45:891, 2005
• In absence of differences in transport status or RRF
incident PD pts followed for 9 months with nutritional
studies and bioimpedance
• Those who decreased their ECW
– Increased their ICW (new or growing cells)
– Had stronger nutritional indices
– Decreased CRP
• Those who increased their ECW
– Increased their ICW at first, then stopped
– Had weaker nutritional indices
– Increased CRP
Does ECW excess swell the bowel and lead to
inflammation and poor nutrition?

45. What are we to do then?

46. Failure To Maintain Volume
Homeostasis
Excessive Sodium and Water intake
• The initial more liberal sodium and fluid diet for PD
patients, compared to HD patients, should be
frequently reassessed, must not be abused, and maybe
should be abandoned entirely
– Fine et al (JASN 8:1311, 1997) in a double-blinded
study gave 60 mEq/d of extra Na to CAPD pts and
BP ONLY rose 9/5 (p < 0.05)
• Clearly, as RRF decreases, patients must be advised to
reduce Na and fluid intake.

47. Diuretics In PD Patients
in the Acute Setting
Van Olden et al PDI 23:339, 2003
Change From Baseline after 2 g/day of
Furosemide for 2 days
Urine volume (mL/day)  500
Urine Na (mmol/day)  by 54
GFR (mL/min) no change

48. Chronic Diuretics In CAPD Pts
Medcalf et al KI 59:1128, 2001
61 incident CAPD pts randomly assigned to furosemide
250 mg/day or to no diuretic
Diuretic
Diuretics had no effect
P < 0.05 on either urea or creatinine
Control clearances

49. High Dose Diuretics
• Gerlag and van Meijel Arch Int Med 148:286, 1988
– Refractory CHF , up to 4000 mg/d continuous intravenous
furosemide in 35 patients, those that survived the to
discharge on doses changed to 2500 mg/d orally
– No observed tinnitus or ototoxicity, most frequent
complication was hypokalemia (31/35)
• Kuchar and O'Rourke Eur Heart J 6: 954, 1985
– Refractory CHF,up to 8000 mg/d continuous intravenous
furosemide in 24 patients, maintenance doses up to 3000
mg/d orally
– Transient tinnitus was observed in 1 patient.

50. High Dose Diuretics
• Brown, Ogg, and Cameron Clin Nephrol 15: 90, 1981
– RCT 56 ARF patients on HD or PD to two different
regimens of furosemide, (1) furosemide 4 mg/min x 4
hr, or (2) furosemide 4 mg/min x 4 h followed by 2
mg/min continuously (up to 3.4 g/d) or 1 g tid PO to
maintain urine output at 150-200 mL/hr and/or SCr <
3.4 mg/dL
– 2 developed ototoxicity while on long-term furosemide
therapy
– 1 developed irreversible deafness on day 11 after a
clerical error led to 12 mg/min furosemide for 3 days
(17.3 g/d)
– Another developed transient deafness after 11 days

51. Oral Furosemide Packaging in Europe

52. Long Term Safety of Diuretics in PD
Faller and Lameire NDT 9:280, 1994
• 7 year observational study comparing two centers
• At the center where diuretics were used 3 of 11 long term
pts became anuric
Vs.
• At the center where diuretics were not used 9 of 12 long
term pts became anuric
• Diuretics routinely recommended by Lameire and Van
Biesen (PDI 21:206, 2001) and Toronto (Khandelwal et al
Adv PD 19:44, 2003) and my patients in Nashville

53. Reversal Of Target Organ Damage
Konings C., et al. Kidney Int. 63:1556, 2003

54. Does Dry Weight Reduction Lower BP?
Dry-Weight Reduction In Hypertensive Hemodialysis Patients
(DRIP)
Agarwal et al Hypertension 53:on line, 2009
• RCT of sophisticated UF attack in 100 randomized to
UF vs. 50 controls
• Average UF over 8 weeks was 1 kg
• Systolic BP reduced 7 mmHg
– Odds ratio for systolic BP reduction in UF pts over
controls was 2.24
• Increase in side effects, but Quality of Life scores were
not different

55. 6th Accord Workshop (Europe)
Locatelli et al NDT 19:1058, 2004
• Target 140/90 or the lowest possible values that
are well tolerated
• Pathophysiologic cornerstone to HT in dialysis pts
is Na-sensitive volume
• Achieve dry wt, via diet and dialysis prescription
• Then use pharmacologic intervention
– RAAS blockers first

56. 6th Accord Workshop (Europe)
Locatelli et al NDT 19:1058, 2004
• Target 140/90 or the lowest possible values that
are well tolerated
• Pathophysiologic cornerstone to HT in dialysis pts
is Na-sensitive volume
• Achieve dry wt, via diet and dialysis prescription
• Then use pharmacologic intervention
– RAAS blockers first