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. 2016 in press.

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. 2016 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. 61 (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.

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. 2016 in press.

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. 2016 in press.

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. 2016 in press.

Study flow diagram 103,895 incident in-center HD patients who were treated with the thrice-weekly schedule (2007-2010) 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. 2016 in press.

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. 2016 in press.

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. 2016 in press.

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. 2016 in press.

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. 2016 in press.

Figure 1. The mortality risk associated with CLurea at one year after initiating HD among 6,538 incident patients (2007-2010) 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. 2016 in press.

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. 2016 in press.

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 (2007-2010) 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. 2016 in press.

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 (2007-2010) 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. 2016 in press.

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. 2016 in press.

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. 2016 in press.

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. 2016 in press.