1. Residual Kidney Function Decline and Mortality
in Incident Hemodialysis Patients
Yoshitsugu Obi, Connie M. Rhee,
Anna T. Mathew, Gaurang Shah, Elani Streja,
Steven M. Brunelli, Csaba P. Kovesdy,
Rajnish Mehrotra, and Kamyar Kalantar-Zadeh.
J Am Soc Nephrol in press.

2. Obi Y, Rhee CM, Mathew AT, …, and Kalantar-Zadeh K
Obi Y, Rhee CM, Mathew AT, …, and Kalantar-Zadeh K.  Residual Kidney Function Decline and Mortality in Incident Dialysis Patients. J Am Soc Nephrol in press.
Background: The importance of preserving RKF in patients on peritoneal dialysis is widely known, but only a few studies have examined RKF in hemodialysis patients. Results: Among included 6,538 incident hemodialysis patients, the median (IQR) baseline value and the mean±SD annual change of CLurea were 3.3 (1.9, 5.0) mL/min/1.73m2 and -1.1±2.8 mL/min/1.73m2, respectively. Greater CLurea at one year after hemodialysis initiation was associated with better survival. Furthermore, loss of RKF showed a gradient association with all-cause mortality; -6.0, -3.0, ±0.0, and +3.0 mL/min/1.73m2/year in CLurea showed case-mix adjusted HRs (95%CIs) of 2.00 (1.55–2.59), 1.25 (1.16–1.35), 0.81 (0.73–0.91), and (0.50–0.74), respectively (reference: -1.5 mL/min/1.73m2/year). These associations were robust against further adjustment for laboratory variables and ultrafiltration rate and were consistent across strata of several pre-specified subgroups. Sensitivity analyses using urine volume as another index of RKF yielded consistent associations. Conclusions: RKF decline during the first year of dialysis showed a graded association with all-cause mortality among incident hemodialysis patients. Future trials are warranted to test the clinical benefits of RKF preservation strategies on mortality.

3. Background (1)
Residual kidney function (RKF), even at such low levels as in patients undergoing maintenance dialysis, substantially contributes to solute clearance particularly for protein-bound solutes and “middle” molecules.
It has been shown that RKF is more strongly associated with survival vs. dialysis clearance in PD.
Although this may also be the case in hemodialysis patients, there is paucity of such data.
Obi Y, Rhee CM, Mathew AT, …, and Kalantar-Zadeh K.  Residual Kidney Function Decline and Mortality in Incident Dialysis Patients. J Am Soc Nephrol in press.

4. Background (2) Other benefits conferred by RKF include ...
Better fluid and metabolic homeostasis
Less severity of mineral and bone abnormalities
Greater endogenous production of erythropoietin
Greater endogenous production of calcitriol
These factors allow for greater fluid and dietary liberalization in this population, and may prevent common complications in ESRD such as LVH, arterial calcification, and congestive heart failure.
Obi Y, Rhee CM, Mathew AT, …, and Kalantar-Zadeh K.  Residual Kidney Function Decline and Mortality in Incident Dialysis Patients. J Am Soc Nephrol in press.

5. Background (3)
Up to 45% of patients in the US initiate HD at eGFR >10 mL/min/1.73m2.
Paucity of prior study in this area may in part be due to misconceptions that RKF declines rapidly after starting maintenance HD, when in fact the rates of RKF decline in HD patients may be similar to patients on PD if the current standard biocompatible membranes and bicarbonate buffer is used.
Annual Data Report from USRDS 2013
In addition, timed urine collections for patients undergoing maintenance HD are labor-intensive and hence, are not performed routinely. This is likely another important reason for the paucity of studies of RKF in HD patients.
Obi Y, Rhee CM, Mathew AT, …, and Kalantar-Zadeh K.  Residual Kidney Function Decline and Mortality in Incident Dialysis Patients. J Am Soc Nephrol in press.

6. Study flow diagram
103,895 incident in-center HD patients who were treated with the thrice-weekly schedule ( )
25,161 censored during the first year
1,071 with prior transplantation
77,663
10,412 ever received dialysis modalities
other than in-center conventional HD
67,311
44,416 without CLurea measurement at the 1st PQ
22,895
16,357 without CLurea measurement at the 5th PQ
6,538 incident in-center HD patients who were treated with the thrice-weekly schedule during the first 4 PQs and who had CLurea measurements at both 1st and 5th PQs
Obi Y, Rhee CM, Mathew AT, …, and Kalantar-Zadeh K.  Residual Kidney Function Decline and Mortality in Incident Dialysis Patients. J Am Soc Nephrol in press.

7. Annual change in renal Clurea (mL/min/1.73m2)
Table 1. Characteristics of 6,538 incident hemodialysis patients who have urine collection data both at baseline and one year after initiation dialysis stratified by annual change in renal urea clearance (CLurea).
Variable
Total (n=6,538)
Annual change in renal Clurea (mL/min/1.73m2)
Ptrend
<-3
-3 to <-1.5
-1.5 to <0 ≥0
(n=1,134, 17%)
(n=1,444, 22%)
(n=2,073, 32%)
(n=1,887, 29%)
Renal CLurea (mL/min/1.73 m2)
3.4 (IQR: 2.1, 5.1)
6.2 (IQR: 5.2, 7.9)
3.9 (IQR: 3.0, 5.0)
2.6 (IQR: 1.7, 3.8)
2.4 (IQR: 1.3, 3.7)
<0.001
Urine volume (mL/day)
900 (IQR: 550, 1,400)
1,478 (IQR: 1,100, 1,900)
1,075 (IQR: 750, 1,450)
750 (IQR: 500, 1,200)
650 (IQR: 400, 1,050)
Age (years)
62 ± 14
61 ± 14
62 ± 15
63 ± 14
0.001
Male (%)
65%
74%
66%
62%
61%
Race (%)
Non-Hispanic White
56%
57%
55%
53%
58%
0.46
Non-Hispanic Black
25%
23%
26%
0.13
Hispanic and others
19%
20%
21%
16%
0.009
Prinary insurance (%)
Medicare
52%
50%
48%
54%
0.04
Medicaid 7% 6%
0.22
Others
42%
43%
44%
39%
0.15
Access (%)
Central Venous Catheter
68%
64%
72%
AV fistula/graft
27%
30%
Unknown 5%
0.95
Comorbidities (%)
Hypertension
51%
0.007
Diabetes
71%
Congestive heart failure
47%
Atherosclerotic heart disease
17%
15%
0.98
Other cardiovascular disease
18%
0.82
Obi Y, Rhee CM, Mathew AT, …, and Kalantar-Zadeh K.  Residual Kidney Function Decline and Mortality in Incident Dialysis Patients. J Am Soc Nephrol in press.

8. Annual change in renal Clurea (mL/min/1.73m2)
Table 1. (Continued)
Variable
Total (n=6,538)
Annual change in renal Clurea (mL/min/1.73m2)
Ptrend
<-3
-3 to <-1.5
-1.5 to <0 ≥0
(n=1,134, 17%)
(n=1,444, 22%)
(n=2,073, 32%)
(n=1,887, 29%)
Body mass index (kg/m2)
27.7 (IQR: 24.0, 32.8)
27.8 (IQR: 24.4, 32.8)
27.8 (IQR: 23.8, 32.6)
27.4 (IQR: 23.9, 32.4)
27.7 (IQR: 24.2, 33.2)
0.98
Single-pool Kt/V
1.30 ± 0.27
1.23 ± 0.26
1.28 ± 0.27
1.32 ± 0.26
1.34 ± 0.28
<0.001
Ultrafiltration rate (L/hour)
0.58 ± 0.24
0.60 ± 0.24
0.59 ± 0.25
0.59 ± 0.23
0.56 ± 0.23
nPCR (g/kg/day)
1.0 ± 0.3
1.11 ± 0.29
1.05 ± 0.28
0.99 ± 0.27
0.95 ± 0.27
Laboratory variables
Hemoglobin (g/dL)
11.5 ± 1.0
11.6 ± 1.0
11.5 ± 1.1
0.02
Albumin (mg/dL)
3.64 ± 0.42
3.59 ± 0.44
3.62 ± 0.43
3.65 ± 0.40
3.67 ± 0.41
Creatinine (mg/dL)
6.0 ± 2.2
5.2 ± 1.8
6.0 ± 2.1
6.4 ± 2.4
Calcium (mg/dL)
9.1 ± 0.5
0.006
Phosphorus (mg/dL)
5.1 ± 1.1
4.9 ± 1.0
5.2 ± 1.1
5.0 ± 1.0
0.08
Intact PTH (pg/mL)
313 (IQR: 207, 461)
292 (IQR: 195, 420)
326 (IQR: 208, 485)
328 (IQR: 218, 482)
303 (IQR: 201, 441)
0.31
Iron saturation (%)
23 ± 8
22 ± 7
23 ± 7
22 ± 8
0.80
Ferritin (pg/nL)
243 (IQR: 140, 403)
219 (IQR: 136, 364)
230 (IQR: 132, 380)
249 (IQR: 141, 401)
258 (IQR: 148, 437)
Bicarbonate (mmol/L)
23.2 ± 2.5
23.1 ± 2.5
23.4 ± 2.5
0.003
Obi Y, Rhee CM, Mathew AT, …, and Kalantar-Zadeh K.  Residual Kidney Function Decline and Mortality in Incident Dialysis Patients. J Am Soc Nephrol in press.

9. Case-mix adjusted model
Table 2. Association of baseline characteristics with annual change in residual renal urea clearance (Clurea).
Case-mix adjusted model
Fully adjusted model
β (95%CI) P
Baseline renal CLurea (per 1.0 mL/min/1.73 m2)
-0.62 (-0.65 to -0.59)
<0.001
-0.70 (-0.74 to -0.67)
Age (years)
<50
-0.11 (-0.26 to 0.05)
0.17
0.17 (0.01 to 0.32)
0.04
50 to <60
-0.16 (-0.29 to -0.02)
0.03
-0.04 (-0.18 to 0.10)
0.56
60 to <70
Reference
70 to <80
-0.08 (-0.22 to 0.06)
0.25
-0.19 (-0.33 to -0.05)
0.007
80 or more
-0.29 (-0.46 to -0.11)
0.001
-0.48 (-0.66 to -0.30)
Male
-0.01 (-0.12 to 0.10)
0.90
0.26 (0.15 to 0.38)
Race/Ethnicity
Non-Hispanics white
Non-Hispanics Black
-0.34 (-0.45 to -0.22)
-0.15 (-0.28 to -0.02)
0.02
Hispanics and Others
-0.32 (-0.44 to -0.19)
-0.10 (-0.22 to 0.03)
0.14
Medicare as primary insurance
-0.03 (-0.13 to 0.07)
0.61
-0.04 (-0.14 to 0.05)
0.39
Central venous catheter use
0.09 (-0.01 to 0.19)
0.06
0.19 (0.09 to 0.29)
Comorbidities
Hypertension
0.53
-0.01 (-0.11 to 0.09)
0.86
Diabetes
-0.16 (-0.27 to -0.05)
0.004
-0.20 (-0.31 to -0.08)
Congestive heart failure
-0.31 (-0.41 to -0.21)
-0.27 (-0.37 to -0.18)
Atherosclerotic heart disease
0.18 (0.03 to 0.34)
0.19 (0.04 to 0.34)
0.01
Other cardiovascular disease
0.01 (-0.13 to 0.16)
0.87
-0.02 (-0.16 to 0.12)
0.77
Single-pool Kt/V (per SD)
0.01 (-0.05 to 0.06)
0.79
0.01 (-0.05 to 0.07)
Body mass index (per SD)
0.09 (0.04 to 0.15)
0.08 (0.02 to 0.14)
0.005
Obi Y, Rhee CM, Mathew AT, …, and Kalantar-Zadeh K.  Residual Kidney Function Decline and Mortality in Incident Dialysis Patients. J Am Soc Nephrol in press.

10. Case-mix adjusted model
Table 2. (Continued)
Case-mix adjusted model
Fully adjusted model
β (95%CI) P
nPCR (g/kg/day)
<0.8
0.27 (0.12 to 0.43)
<0.001
0.19 (0.04 to 0.34)
0.01
0.8 to <1.0
0.04 (-0.09 to 0.18)
0.54
-0.01 (-0.14 to 0.12)
0.87
1.0 to <1.2
Reference
1.2 or more
-0.04 (-0.18 to 0.11)
0.64
0.02 (-0.12 to 0.16)
0.76
Laboratories
Hemoglobin (per SD)
0.07 (0.02 to 0.12)
0.005
0.05 (-0.01 to 0.10)
0.09
Albumin (g/dL)
<3.2
-0.56 (-0.70 to -0.41)
-0.73 (-0.89 to -0.58)
3.2 to <3.6
-0.28 (-0.40 to -0.16)
-0.36 (-0.48 to -0.24)
3.6 to <4.0
4.0 or more
0.07 (0.03 to 0.12)
0.002
0.34 (0.20 to 0.48)
Creatinine (per SD)
-0.39 (-0.45 to -0.33)
-0.38 (-0.45 to -0.31)
Calcium (per SD)
0.08 (0.03 to 0.13)
Phosphorus (per SD)
-0.30 (-0.35 to -0.25)
-0.17 (-0.22 to -0.11)
Intact PTH (pg/mL)
<160
0.28 (0.12 to 0.44)
0.001
0.12 (-0.04 to 0.28)
0.14
160 to <320
0.23 (0.11 to 0.34)
0.13 (0.01 to 0.24)
0.03
320 to <640
640 or more
-0.25 (-0.38 to -0.12)
-0.13 (-0.26 to 0.00)
0.04
Iron saturation (per SD)
-0.05 (-0.10 to 0.00)
-0.07 (-0.12 to -0.02)
0.006
Ferritin (ng/mL)
<200
-0.09 (-0.23 to 0.04)
0.18
-0.11 (-0.24 to 0.03)
0.12
200 to <400
-0.05 (-0.19 to 0.09)
0.49
0.46
400 to <800
800 or more
0.19 (-0.08 to 0.45)
0.16
0.25 (-0.01 to 0.51)
0.06
Bicarbonate (per SD)
0.01 (-0.04 to 0.06)
0.60
-0.13 (-0.18 to -0.08)
Obi Y, Rhee CM, Mathew AT, …, and Kalantar-Zadeh K.  Residual Kidney Function Decline and Mortality in Incident Dialysis Patients. J Am Soc Nephrol in press.

11. Figure 1. The mortality risk associated with CLurea at one year after initiating HD among 6,538 incident patients ( ) with 3-level adjustments.
Ptrend <0.001
in all models
CLurea at 1 year (mL/min/1.73m2)
Obi Y, Rhee CM, Mathew AT, …, and Kalantar-Zadeh K.  Residual Kidney Function Decline and Mortality in Incident Dialysis Patients. J Am Soc Nephrol in press.

12. Robust against adjustments
Figure 2. Distributions and restricted cubic splines comparing the relationship of annual change in CLurea with all-cause mortality among 6,538 incident hemodialysis; (A) baseline renal CLurea adjustment model, (B) case-mix adjustment model, (C) fully-adjusted model, and (D) additional adjustment for baseline ultrafiltration rate (UFr) and its annual change on the fully-adjusted model.
Robust against adjustments
Obi Y, Rhee CM, Mathew AT, …, and Kalantar-Zadeh K.  Residual Kidney Function Decline and Mortality in Incident Dialysis Patients. J Am Soc Nephrol in press.

13. Robust against baseline levels
Figure 3. Distributions and casemix-adjusted all-cause death hazard ratios of annual change in CLurea among 6,538 incident hemodialysis patients ( ) stratified by baseline CLurea levels.
Robust against baseline levels
Obi Y, Rhee CM, Mathew AT, …, and Kalantar-Zadeh K.  Residual Kidney Function Decline and Mortality in Incident Dialysis Patients. J Am Soc Nephrol in press.

14. Robust against subgroup analyses
Figure 4. Over all and subgroup analyses of association between rapid decline in CLurea >3 mL/min/1.73m2/year and all-cause mortality among 6,538 incident HD patients ( ) in the case-mix adjustment model.
Robust against
subgroup analyses
Obi Y, Rhee CM, Mathew AT, …, and Kalantar-Zadeh K.  Residual Kidney Function Decline and Mortality in Incident Dialysis Patients. J Am Soc Nephrol in press.

15. The same is true with urine volume (sensitivity analyses)
Obi Y, Rhee CM, Mathew AT, …, and Kalantar-Zadeh K.  Residual Kidney Function Decline and Mortality in Incident Dialysis Patients. J Am Soc Nephrol in press.

16. Clinical implications
Given the exclusion of RKF from the recent ESRD Quality Incentive Program's (QIP) assessment of HD adequacy, our findings are both timely and relevant.
At this time, the only metric considered in the ascertainment of HD adequacy is single-pool Kt/V with a threshold of ≥1.2.
However, many patients early in their course of ESRD may retain substantial RKF, which may have an important bearing on their achievement of adequate clearance and volume removal, leading to better clinical outcomes.
Furthermore, individualizing HD prescriptions according to RKF may allow for the reduction in HD treatment time and frequency, which may favorably impact patients' QOL and reduce medical costs.
(see Obi et al, AJKD 2016 in press)
Obi Y, Rhee CM, Mathew AT, …, and Kalantar-Zadeh K.  Residual Kidney Function Decline and Mortality in Incident Dialysis Patients. J Am Soc Nephrol in press.

17. Conclusion
Decline in RKF shows a graded association with higher mortality in incident hemodialysis patients.
Future trials are warranted to test the clinical benefits of RKF preservation strategies including maintaining diuretic use and the incremental hemodialysis regimen.
Obi Y, Rhee CM, Mathew AT, …, and Kalantar-Zadeh K.  Residual Kidney Function Decline and Mortality in Incident Dialysis Patients. J Am Soc Nephrol in press.