Effect of Intradialytic Parenteral Nutrition on Mortality Rates in End-Stage Renal Disease Care

Effect of Intradialytic Parenteral Nutrition on Mortality Rates in End-Stage Renal Disease Care John P. Capelli, MD, Harvey Kushner, PhD, Theodore C. Camiscioli, MD, Shwu-Miin Chen, MD, and Mario A. Torres, MD • Several studies have now demonstrated that low serum albumin and/or low protein catabolic rates correlate with increased risk of death in the chronic hemodialysis patient. A study involving 81 patients receiving thrice-weekly hemodialysis treatments and who had either a low serum albumin and/or protein catabolic rate was conducted to compare the effect of intradialytic parenteral nutrition (IDPN) on mortality rates. Fifty patients received IDPN and 31 patients did not. Thirty-eight of the patients were black (47%), 34 were white (42%), and 9 were Hispanic (11%). The study included 33 diabetic patients (41%),20 of whom received IDPN. Nondiabetic patients received an average of 725 kcal/hemodialysis treatment and diabetic patients received an average of 670 kcal/hemodialysis treatment. The average length of treatment was 9 months. The results of the study revealed a better survival rate (64% v 52%) for patients treated with IDPN. Using Cox analysis, the IDPN-treated group had a significantly better survival rate (P < 0.01). Serum albumin increased by 12% in the survivors. There was no difference in survival when considered separately for diabetic and nondiabetic patients who received IDPN (mortality rate for diabetics: 50% for treated patients and 54% for untreated patients; mortality rate for nondiabetics: 26% for treated patients and 44% for untreated patients). However, the nondiabetic treated patients had the lowest mortality rates. In conclusion, correction of hypoalbuminemia by IDPN significantly reduced mortality rates overall. © 1994 by the National Kidney Foundation, Inc. INDEX WORDS: Hemodialysis; nutrition; parenteral nutrition; survival; hemodialysis.

T

HE ROLE OF nutrition as a significant risk factor in the outcome of care for the endstage renal disease (ESRD) patient was clearly demonstrated by the National Dialysis Cooperative Study on the adequacy of dialysis. I ,2 Depressed KtjV «0.8) and protein catabolic rate (PCRn) «0.9) were previously associated with increased morbidity and mortality. In subsequent years, further studies demonstrated the specific relationship of depressed serum albumin, a marker of protein caloric malnutrition, and increased mortality.3,4 However, before the National Dialysis Cooperative Study on the adequacy of dialysis, numerous studies documented the high incidence of malnutrition in patients undergoing maintenance hemodialysis,5-7 Thus, while it is clear that malnutrition in the ESRD patient is associated with a higher mortality rate, From the Department ofMedicine, Division ofNephrology, Our Lady of Lourdes Medical Center, Camden, NJ; and the Department of Biostatistics, Hahnemann University, Philadelphia, PA. Received April 23, 1993; accepted in revisedform February 15, 1994. Presented at the Poster Session of the annual meeting of the American Society of Nephrology, 1992, Baltimore, MD. Address reprint requests to John P. Capelli, MD, Division of Nephrology, Our Lady of Lourdes Medical Center, 1600 Haddon Ave, Camden, NJ 08103. © 1994 by the National Kidney Foundation, Inc. 0272-6386/94/2306-0007$3.00;0 808

a standardized approach to therapy is still under study. Efforts to improve the nutritional status of the chronic dialysis patient have involved different strategies that have been driven significantly by economic considerations. 8 Therapies have ranged from simple dietary counseling, to nutritional supplements, and finally to intradialytic parenteral nutrition (IDPN). Studies, limited in number, have shown no significant benefit from oral nutritional supplements. 9 ,1D This has caused investigators to use parenteral therapy to better manage the malnutrition in these patients. While there is some evidence that IDPN may be beneficial, the studies to date are still unclear as to the effect on decreasing mortality rates. I I This report is based on a nonrandomized retrospective study of 81 patients. The effect of this therapy on serum albumin, body weight, and mortality was analyzed. In addition, the 33 diabetic patients in this study were analyzed as a separate subgroup. MATERIALS AND METHODS

Patient Caseload Eighty-one patients were included in this study. All patients were maintained on thrice-weekly chronic hemodialysis treatments at the Regional Artificial Kidney Center of Our Lady of Lourdes Medical Center. The study period lasted 24 months. Treated patients all had depressed serum albumins (ie, <3.5 gjdL) and at least one of the following findings: (1) an actual

American Journal of Kidney Diseases, Vol 23, No 6 (June), 1994: pp 808-816

IDPN AND ESRD SURVIVAL

body weight of at least 10% below calculated ideal body weight and/or (2) 10% or more total weight loss extending over 2 consecutive months. If there was no response to dietary counseling and/or supplements after 2 months, IDPN was then initiated. These patients constituted the treated group of patients. The untreated patients were those who also had depressed serum albumin but whose ideal body weight or weight loss was not consistently below the 10% limits. These patients did not receive IDPN and served as controls. Fifty patients received IDPN.

Dietary and Nutritional Evaluation All patients had previously received nutritional instructions by certified dietitians advising diets with sufficient protein content and calories, but low in fat, salt, and potassium. Chronic hemodialysis patients received daily multivitamins high in B complex and supplemental folic acid. On a monthly basis, each patient in the total dialysis population has a blood chemistry examination, which includes a complete blood cell count and a chemistry profile of 20 analytes (electrolytes, blood urea nitrogen, creatinine, SGOT, SGPT, liver profile, total proteins, albumin, cholesterol, triglycerides, iron, and transferrin). Urea kinetic modeling (ie, Kt/V and PCRn) is also calculated. Monthly reports listing abnormalities in albumin, Kt/V, PCRn, calcium, phosphorus, and potassium levels were produced and reviewed individually by the nursing staff, dietitians, and physicians. Patients demonstrating abnormal KtjV and PCRn (ie, < 1.0 and 0.9, respectively) were subjected to corrected dialysis prescriptions. If the albumin values were depressed despite normal Kt/V, then dietary counseling took place. Patients were given dietary supplements in the form ofNepro (Russ Laboratories, Columbus, OH), Ensure-Plus (Russ Laboratories), and/or Ensure (Russ Laboratories). Dietary supplements were discontinued if IDPN was initiated. In the untreated groups, continuous dietary supplements were prescribed, but poor patient compliance generally led to discontinuance after 3 months.

809 Table 1. Intradialytic Parenteral Nutrition Regimens

Nondiabetic patients 50% Dextrose: 950 NP kcal/L 500mL 250mL 250mL 50% Dextrose: 725 NP kcal/L 500 mL 250mL 250mL 50% Dextrose: 470 NP kcal/0.75 L 500mL 150 mL 100 mL Diabetic patients 20% Dextrose: 670 NP kcal/L 500mL 250mL 250mL 20% Dextrose: 445 NP kcal/L 500 mL 250mL 250 mL 20% Dextrose: 302 NP kcal/0.75 L 500 mL 150 mL 100 mL

10% AA = 50 9 protein 50% D = 450 NP kcal 20% lipid = 500 NP kcal

10% AA = 50 9 protein 50% D = 450 NP kcal 10% lipid = 275 NP kcal

10% AA = 50 9 protein 50% D = 270 NP kcal 20% lipid = 200 NP kcal

10% AA = 50 9 protein 20% D = 170 NP kcal 20% lipid = 500 NP kcal

10% AA = 50 9 protein 20% D = 170 NP kcal 10% lipid = 275 NP kcal

10% AA = 50 9 protein 20% D = 102 NP kcal 20% lipid = 200 NP kcal

NOTE. All solutions contained trace elements, B complex multivitamins, and 6 to 8 U humulin insulin (regular, 100 U). Abbreviations: NP, nonprotein; AA, amino acid; D, dextrose.

Intradialytic Parenteral Nutrition Therapy Patients received IDPN during the course of their regularly scheduled dialysis treatments. The solutions were prepared by the hospital pharmacy and delivered the day of the treatment (Table I). The nondiabetic patients received 50% dextrose concentrations and the diabetic patients received 20% dextrose concentrations. All patients received 10% essential amino acids with either 10% or 20% lipids. Seventy-five millimoles of NaCI/L, trace elements, and 6 to 8 U of regular insulin were added to each bag. Depending on the patient's dialysis time (ie, 2 to 4 hours per treatment), the patients received 750 to 1,000 mL of the solution during their dialytic treatment. The nondiabetic patients received an average of725 kcal per hemodialysis treatment and the diabetic patients received 670 kcal per hemodialysis treatment. The average length of treatment with IDPN was 9 months.

Kinetic Modeling Each patient was modeled at least monthly unless their outpatient care was interrupted by hospital admission or travel

to another facility. Theoretical Kt/V modeling was accomplished initially and monthly to determine a dialysis prescription that would achieve a KtjV of 1.2. To determine the patient's actual KtjV, we utilized the urea kinetic modeling formula developed by Jindal et ai, 12 which uses a linear regression equation in which the variable function is the percentage of reduction of urea, and the formula developed by Gotch and Keen 13 for protein catabolic rate, taking into account residual renal function. The formulae were programmed for computer application, and the appropriate data for each patient were computed by the respective nursing staff. Initially, all patients were modeled, and patient dialysis prescriptions were altered to achieve a KtjV of 1.0 to 1.2 and a normalized PCR (PCRn = PCR/kg body weight) of 0.9 to 1.1. Kinetic modeling was accomplished using midweek predialysis to postdialysis blood urea nitrogen measurements, ie, at the beginning and at the end of the midweek dialysis treatment. All patients were kinetically modeled at least monthly or more frequently, depending on the results. The results were reviewed by the medical, nursing, and dietary staffs

CAPELLI ET AL

810

Table 2. Total Caseload Demographics: Intradialytic Parenteral Nutrition-Treated Versus Nontreated Patients Treated

Untreated Patients

Total Patients

Probability Value

50 59.4 ± 14.2

31 60.4 ± 14.1

81 59.8 ± 14.1

0.77

Male(%) Female(%)

27 (54) 23 (46)

14 (45) 17 (55)

41 (51) 40 (49)

0.44

White(%) Black(%) Hispanic (%)

22(44) 23 (46) 5 (10)

12 (39) 15 (48) 4 (13)

34(42) 38(47) 9 (11)

0.40

Diabetic (%) Nondiabetic (%)

20 (40) 30 (60)

13 (42) 18 (58)

33 (41) 48(59)

0.86

3.1 ± 3.8

0.18

No. of patients Age (yr)*

No. of years on dialysis

3.45 ± 4.0

2.35 ± 3.3

• Mean ± SO.

at a monthly multidisciplinary quality assurance committee meeting. For those patients who had low KtjV, with or without low PCRn, physician-directed adjustments in the dialysis prescription took place by theoretically remodeling the patient against a KtjV of 1.2 and changing either dialyzer, time, and/ or blood rates. Usually, the most common adjusted parameter was an increased blood flow rate. If a 25% or greater reduction in KtjV was observed in a I-month interval, the percentage of recirculation was calculated to investigate possible deterioration of graft function. For patients with abnormal PCRn, the patient's serum albumin was also matched to determine if the value(s) were below 3.5 gJdL. For these patients, adjustments to their dialysis prescriptions were undertaken if their KtjV also was less than 1.0 before IOPN was considered.

Statistics All patient data were maintained in a clinical research dialysis computer system (Capcom, Haddonfield, NJ). ASCII files were exported from the dialysis information system to SPSS/PC (SPSS Inc, Chicago, IL) for statistical analysis. A two-way analysis of variance (ANOV A) was used to compare means between diabetic and nondiabetic patients and between treated and untreated patients. A two-way ANOVA also was used to compare mean values between survivors and nonsurvivors and between treated and untreated patients. The mean values are listed as mean ± so. Graphs are presented with the mean ± SEM. Comparison of proportions was performed using the chi-squared test. Survival analysis between treated and untreated cases was examined further using the Cox proportional hazards model. In the proportional hazards model, all possible factors, including age, diabetes, IOPN treatment, weight, change in weight, albumin, KtjV, PCRn, length of time on dialysis, sex, and race, were entered into the analysis. Results were considered statistically significant for P < 0.05. Survival analysis was performed using SAS version 6.03 (SAS Institute, Cary, NC).

RESULTS

Patient Demographics The demographic data included age, sex, race, diabetic status, and number of years on dialytic

therapy (Table 2). The patient caseload was further classified into diabetic or nondiabetic status with an analysis of the same demographic factors (Table 3). Hypertensive nephrosclerosis accounted for 32 cases; 33 cases of diabetes mellitus, types I and II. Chronic glomerulonephritis and interstitial nephritis accounted for eight cases; the remaining eight cases were of varying etiologies (Table 4). There were no cases of malignancy included in these groups. There were no statistically significant demographic differences noted between groups (ie, treated v untreated, diabetic treated/diabetic untreated v nondiabetic treated/nondiabetic untreated), with the exception of the length of time on dialysis for diabetic patients (Table 3). For the total caseload, there was a significantly shorter time to death in the nonsurvivors receiving no treatment. Nutritional Results: Total Caseload Body weights. The resulting changes in body weight are summarized in Table 5. The mean body weight in the survivors 1 month prior to the initiation of IDPN therapy was 142.9 ± 35 lb in the treated group and 151.1 ± 33 lb in the untreated group (Table 5). Weights had increased to 157.3 ± 40 lb and 168.7 ± 44lb in this treated group at 8 and 12 months, respectively. These represent 14- to 26-lb weight gains and were statistically significant at the 0.01 level. In the untreated survivors, there were no significant changes in weight from baseline to the end of the

811

IOPN ANO ESRO SURVIVAL Table 3. Diabetic Caseload: Intradialytic Perenteral Nutrition-Treated Versus Nontreated Patients Diabetics

Nondiabetics

Probability Value

Treated

Untreated

Treated

Untreated

Diabetics

Treated

20 62.8 ± 11.0

13 60.0 ± 10.4

30 57.2 ± 15.8

18 60.7 ± 16.5

0.32

0.78

Male(%) Female(%)

9 (45) 11 (55)

5 (38) 8 (62)

18 (60) 12 (40)

9 (50) 9 (50)

0.22

White(%) Black(%) Hispanic (%)

8 (40) 9 (45) 3 (15)

5 (38) 7 (54) 1 (8)

14 (47) 14 (47) 2 (6)

4 (22) 11 (61) 3 (17)

0.94

2.1 ± 1.7

1.6 ± 2.3

4.5 ± 4.8

2.9 ± 3.8

0.02'

No. of patients Age (yr)

No. of years on dialysis

0.18

, Two-way ANOVA for age and no. of years on dialysis; there was no statistically significant interactions for the ANOVA analyses. Chi-squared test for sex and race. Means are expressed as mean ± SO.

study. The mean weight in this group was 150.1 ± 33 lb initially and 148.1 ± 24 lb at the end of the study (Table 5). The results of the body weights in the nonsurvivors are presented in Table 5. In this group, those treated with IDPN did not show any appreciable weight gains, ie, 115.9 ± 25lb pretreatment and 121.3 ± 15 lb and 122 ± 18 lb at the end of 8 months and 12 months of therapy, respectively. The untreated patients in this nonsurvivor group also had an essentially unchanged body weight, ie, 137.9 ± 38lb initially and 133.3 ± 39 and 139.2 ± 40 lb at 8 and 12 months, respectively. There was a significant difference in the baseline body weights between the survivors and nonsurvivors (143.9 ± 35 lb v 115.9 ± 25 lb) (P = 0.02). The untreated nonsurvivors had significantly lower body weights at the end of 8 months (133.3 ± 39 Ib) as opposed to the untreated surTable 4. Primary Diagnosis: Intradialytic Parenteral Nutrition Study Groups Treated Patients (%J Untreated Patients (%J

OM 1/11 HN GN/ISN CRF, unspecified Others

20(40) 21 (40) 4 (10)

13 (42) 11 (36) 4 (13)

2 (4) 3 (6)

2 (6) 1 (3)

Abbreviations: OM, diabetes mellitus; HN, hypertensive nephrosclerosis; GN, glomerulonephritis; ISN, interstitial nephritis; CRF, chronic renal failure.

vivors, who had a mean body weight of 147.6 ± 24 lb at 8 months (P = 0.05). Serum albumin. The results in serum albumin are summarized in Table 5. The mean serum albumin levels were below normal before initiation of IDPN for all four groups (treated and untreated survivors and treated and untreated nonsurvivors), ranging from 2.83 ± 0.48 g/dL to 3.08 ± 0.58 g/dL. Although the values did not achieve statistical significance, the serum albumin in the treated survivor group achieved the highest level of all groups (3.61 ± .32 g/dL after 12 months). The untreated survivors did reach nearnormal serum albumin levels (3.4 ± 0.30 g/dL). The treated and untreated nonsurvivor groups of patients actually showed no change or a slightly lower level of serum albumin, ranging from initial values of 3.04 ± 0.54 g/dL to 3.06 ± 0.36 g/dL and from 2.93 ± 0.25 g/dL to 3.28 ± 0.57 g/dL after therapy, respectively. A significant observation was related to the time required, ie, up to 8 months of therapy, before normal values were achieved in the survivor group. Urea kinetic modeling: total caseload. Urea kinetic modeling, Kt/V, and PCRn data revealed values maintained in an acceptable range, that is, 0.95 ± 0.27 to 1.35 ± 0.57 for Kt/V and 0.90 ± 0.11 to 1.48 ± 0.39 for PCRn (Table 5).

Nutritional Results: Diabetic Caseload Body weight. The resulting changes in body weights, serum albumin, and urea kinetic modeling in the diabetic patients are summarized in

812

CAPELLI ET AL Table 5. Characteristics of Survivors Versus Nonsurvivors in Intradialytic Parenteral Nutrition Treated and Untreated Patients Treated

Time

Untreated

No. of Patients

Weight (Ib)

Albumin (g/dL)

KtN

PeRn

No. of Patients

Weight (Ib)

Albumin (g/dL)

KI/V

PeRn

32

142.9 ± 35

3.08 ± 0.58

0.95 ± 0.27

1.01 ± 0.29

16

151.1 ± 33

2.83 ± 0.48

1.16 ± 0.45

1.06 ± 0.33

32 31 26 22 21

148.2 ± 145.8 ± 148.0 ± 157.3 ± 168.7 ±

3.04 3.16 3.41 3.59 3.61

1.00 ± 1.02 ± 1.08 ± 1.20 ± 1.18 ±

1.10 ± 1.21 ± 1.06 ± 0.93 ± 1.03 ±

0.37 0.43 0.28 0.30 0.40

16 16 12 10

8

149.8 ± 30 149.2 ± 28 147.0 ± 24 147.6 ± 24 148.1 ±24

3.05 ± 2.99 ± 3.42 ± 3.29 ± 3.40 ±

1.24 ± 1.31 ± 1.35 ± 1.17 ± 1.05 ±

0.91 ± 0.99 ± 1.09 ± 1.04 ± 0.97 ±

18

115.9 ± 25

3.04 ± 0.54

1.24 ± 0.36

1.12 ± 0.39

15

137.9 ± 38

3.06 ± 0.36

1.24 ± 0.33

0.94 ± 0.25

18 15 12

117.7±27 117.1 ± 28 130.4 ± 26 121.3 ± 15 122.0± 18

3.28 ± 3.11 ± 3.33 ± 3.00 ± 2.93 ±

1.14 ± 0.98 ± 1.18 ± 0.85 ± 1.12 ±

1.48 ± 1.24 ± 1.22 ± 1.18 ± 0.90 ±

12 10

136.9 ± 134.5 ± 132.0 ± 133.3 ± 139.2 ±

3.19 ± 3.13 ± 3.25 ± 3.22 ± 3.28 ±

1.26 ± 1.10 ± 1.11 ± 1.14 ± 0.9 ±

1.07 ± 1.14 ± 1.11 ± 1.02 ± 1.00 ±

Survivors

Baseline· Posttreatment Mol M03 M06 M08 Mo12

36 36 36 40 44

± ± ± ± ±

0.45 0.60 0.51 0.47 0.32

0.37 0.25 0.25 0.21 0.21

0.49 0.46 0.61 0.68 0.30

0.63 0.65 0.57 0.29 0.36

0.37 0.32 0.26 0.27 0.18

Nonsurvivors

Baseline· Posttreatment Mol M03 M06 M08 Mo12

9 7

0.64 0.68 0.35 0.43 0.25

0.26 0.22 0.49 0.17 0.25

0.39 0.34 0.45 0.37 0.11

5 5 5

37 36 40 39 40

0.41 0.42 0.91 0.32 0.57

0.26 0.35 0.40 0.15 0.32

0.25 0.12 0.25 0.15 0.24

NOTE. The mean values are expressed as mean ± SD . • Baseline represents 1 month before initiation of IDPN therapy. "Mo 1" represents 1 month after initiation of IDPN therapy.

lb) and at the end of8 and 12 months of therapy (156.7 ± 35 lb and 158.7 ± 36 lb, respectively). Serum albumin. The results of serum albumin in the diabetic caseload are summarized in Table 6. The mean serum albumin in the diabetic patients also was below normal prior to initiation ofIDPN (3.13 ± 0.44 g/dL) and slightly above that of the nondiabetic patients (2.94 ± 0.56 g/

Table 6. The mean body weight of the diabetic group was 146.9 ± 37 lb compared with 133.6 ± 32 lb for the nondiabetic group. However, the diabetic treated group showed very significant weight gains at 8 months (160.5 ± 50 lb; P = 0.02) and 12 months (184.3 ± 50 lb; P = 0.01) The diabetic untreated patients showed no substantial change in weight from their baseline (157.8 ± 39

Table 6. Characteristics of Intradialytic Parenteral Nutrition-Treated and Untreated Diabetic Patients Treated

Time Diabetic patients Baseline" Posttreatment Mol M03 M06 M08 Mo12 Nondiabetic patients Baseline" Posttreatment Mol M03 M06 M08 Mo12

Untreated

No. of Patients

Weight (Ib)

Albumin (g/dL)

Kt/V

PeRn

No. of Patients

Weight (Ib)

Albumin (g/dL)

KtN

PeRn

20

136.1 ± 35

3.19 ± 0.43

1.06 ± 0.38

1.03 ± 0.30

13

157.8 ± 39

3.04 ± 0.45

1.13 ± 0.20

0.88 ± 0.28

20 19 16 13 12

135.7 ± 138.0 ± 152.4 ± 160.5 ± 184.3 ±

3.31 ± 3.31 ± 3.54 ± 3.40 ± 3.61 ±

1.11 ± 1.06 ± 0.98 ± 1.11 ± 1.23 ±

1.44 ± 1.30 ± 1.07 ± 0.95 ± 0.97 ±

0.48 0.50 0.31 0.17 0.23

13 11

7 6 6

157.3 ± 39 155.9±35 153.9 ± 35 156.7 ± 35 158.7 ± 36

3.19 ± 3.15 ± 3.66 ± 3.52 ± 3.46 ±

1.05 ± 1.06 ± 1.10 ± 1.21 ± 0.98 ±

0.32 0.58 0.46 0.20 0.29

0.94 ± 0.30 1.11 ±0.30 1.06 ± 0.20 1.00 ± 0.17 0.98 ± 0.17

30

132.9 ± 34

2.99 ± 0.63

1.04 ± 0.30

1.05 ± 0.34

18

134.3 ± 30

2.87 ± 0.43

1.25 ± 0.46

1.07 ± 0.28

138.0 ± 36 133.3 ± 34 136.1 ±28 136.9 ± 24 137.6 ± 27

3.00 ± 3.03 ± 3.31 ± 3.48 ± 3.40 ±

0.99 ± 0.97 ± 1.22 ± 1.23 ± 1.11 ±

1.08 ± 1.18 ± 1.11 ± 1.03 ± 1.15 ±

17 15 10

133.6 ± 132.1 ± 129.6 ± 130.4 ± 133.8 ±

3.06 3.00 3.12 3.09 3.27

1.42 1.35 1.39 1.11 1.06

1.00 1.02 1.12 1.07 0.98

30 27 21 18 16

37 39 40 50 50

0.41 0.57 0.43 0.40 0.67

0.41 0.65 0.48 0.55 0.37

0.40 0.24 0.23 0.22 0.16

0.28 0.23 0.37 0.23 0.25

0.27 0.30 0.34 0.26 0.45

9 7

28 28 27 26 25

NOTE. Mean values are expressed as mean ± SD. " Baseline represents 1 month before initiation of IDPN therapy. "Mo 1" represents 1 month after initiation of IDPN therapy.

0.48 0.32 0.44 0.50 0.41

0.44 0.50 0.85 0.50 0.50

0.58 0.46 0.54 0.27 0.38

0.31 0.21 0.29 0.28 0.24

813

IOPN ANO ESRO SURVIVAL Table 7. Total Caseload: Survivors Versus Nonsurvivors by Treatment Status Survivors

Nonsurvivors

Probability

Treated

Untreated

Treated

Untreated

Survival

Treatment

32 58.8 ± 14.6

16 59.6 ± 15.5

18 60.6 ± 13.9

15 61.3 ± 12.9

0.59

0.82

Male(%) Female(%)

17 (53) 15 (47)

9(56) 7(44)

10 (56) 8(44)

5 (33) 10 (67)

0.44

White(%) Black(%) Hispanic (%)

13 (41) 15 (47) 4 (12)

4 (25) 11 (69) 1 (6)

9 (50) 8 (44) 1 (6)

5 (33) 7(47) 3 (20)

0.74

3.8 ± 4.3

1.8 ± 2.8

No. of patients Age (yr) (mean ± SO)

No. of years on dialysis Time to death (mo) for nonsurvivors'

3.1 ± 3.7

2.9 ± 3.7

16.9 ± 7.9

7.5 ± 4.2

0.98

0.19 0.01

NOTE. Two-way ANOVA was used to analyze age and number of years on dialysis; there were no statistically significant interactions for the ANOVA analyses. The chi-squared test was used to analyze sex and race . • Cox proportional hazards model (see Table 9). Time to death was calculated as the observed average time to death.

dL). However, by the sixth month, the treated diabetic patients had achieved normal serum albumin levels (3.54 ± 0.43 gjdL), and by the twelfth month the level was even higher (3.61 ± 0.67 gjdL). In the untreated diabetic groups, the serum albumin levels improved up to 6 months (3.66 ± 0.44 gjdL), but at 8 and 12 months, decreased to below normal (Table 6). Urea kinetic modeling: diabetic caseload. The KtjV ranged between 0.98 ± 0.23 and 1.23 ± 0.23; PCRn ranged between 0.88 ± 0.28 and 1.44 ± 0.48 in the diabetic patients. There were no statistically significant trends noted with these values.

Survival Analysis: Total Caseload The survival data are summarized in Tables 7, 8, and 9. There was no statistically significant difference in the percentage of deaths between IDPN-treated and -untreated groups. Using the Cox proportional hazards survival analysis (Table 9), a significantly increased survival was observed with the use ofIDPN (relative risk = 1.34; P < 0.01). Using this analysis, no other covariate was statistically significant, ie, only treatment with IDPN significantly affected survival rates. However, a trend was noted in the IDPN-treated nondiabetic patient groups who had a lower mortality rate (26%) than the non-

Table 8. Mortality Rates for Intradialytic Parenteral Nutrition-Treated and Untreated Patients

Total caseload (N) Mortality rate (N) Time to death (mo) (mean ± SO)* No. of diabetic patients Mortality rate (N) Time to death (mo) (mean ± SO) No. of nondiabetic patients Mortality rate (N) Time to death (mo) (mean ± SO):\:

Treated

Untreated

50 36% (18) 16.9 ± 7.9 20 50% (10) 19.4 ± 7.0 30 26%(8) 14.7 ± 8.4

31 48% (15) 7.5 ± 4.2 13 54%(7) 5.9 ± 3.0 18 44%(8) 9.1 ± 4.9

Probability Value

0.27 <0.01t 0.83

0.21

• Time to death refers to nonsurvivors and was calculated as observed time to death. t Cox proportional hazards model (see Table 9). :\: Individual survival tables for diabetic and nondiabetic patients were not considered due to the small sample sizes for the multivariate regression model.

CAPELLI ET AL

814 Table 9. Survival Analysis: Cox Proportional Hazards Regression Model

Variable

Coefficient

Standard Error

Coefficient/SE

Probability Value

Univariate Relative Risk

Treatment PCR month 1 Age of patient Length of time on dialysis (yr) Sex Race Diabetic Body weight mo 1

1.1677 3.9443 -0.0078 0.0834 -0.0499 -0.1280 -0.3401 -0.1286 0.1452 -0.4015

0.4452 2.1973 0.0144 0.0593 0.3785 0.3019 0.3895 0.1074 0.3632 0.7992

2.6227 1.7950 -0.5430 1.4070 -0.1319 -0.4239 -0.8731 -1.1983 0.3997 -0.5023

0.01 0.077 0.59 0.16 0.90 0.68 0.39 0.23 0.69 0.62

1.34 (untreated/treated) 1.28 «0.90/0.90-1.20) 1.68 (>50 yr/<50 yr) 1.13 (> 1 yr/<1 yr) 1.23 (M/F) 1.19 (white/nonwhite) 1.55 (diabetic/nondiabetic) 1.94 «121 Ib/>121 Ib) 0.92 (outside 0.8-1.2/within 0.8-1.2) 1.22 «3.5/>3.5)

KtfV

Albumin mo 1

treated nondiabetic patient group (44%), although it was not statistically significant (P = 0.21). Comparison of case mix between the treated and untreated groups showed no significant differences, with the exception of the length of time on dialysis in the diabetic patients, that is, the date of first dialysis to the date of the initiation of treatment with IDPN. The treated diabetic survivors had been on dialysis for a mean of 2.1 years compared with 1.6 years in the untreated diabetic patients. DISCUSSION

Over the past several years, evidence has accumulated that clearly reflects the occurrence of protein caloric malnutrition in patients undergoing renal replacement (dialytic) therapy.s.7 Concomitant with recognition of this abnormality, several studies,3,4,7 including the National Cooperative Dialysis Study,I,2 confirmed that poor nutrition may contribute to increased morbidity and mortality in maintenance dialysis patients. The level of serum albumin, a protein marker of nutritional status, has been shown to correlate inversely with mortality rate in ESRD patients,3,4 and is a more powerful predictor of death than were urea reduction ratios.14 Several factors have been attributed to the protein caloric malnutrition in these patients, such as anorexia, particularly on dialysis days, with associated nausea and vomiting; nutrient losses into dialysate (eg, 6 to 8 g amino acid/dialysis day); numerous medications and/or uremic toxicity symptoms that interfere with intestinal absorption; dietary restrictions on sodium, potassium, and dairy products that result in protein restric-

tions; and somatic protein degradation in poorly nourished patients. Thus, while there is clear and convincing evidence for the presence and role of malnutrition in the ESRD patient and their survival, such evidence for the treatment of this deficiency with intradialytic parenteral or oral nutrition supplementation is lacking. II In studies using oral supplements, 11,15 no additional benefits were evident from oral essential amino acid supplementation. However, as far back as 1975, Heidland and Kult l6 demonstrated that intradialytic infusions of amino acids in association with high-caloric diets resulted in increases in serum albumin, transferrin, and body weights in 18 patients. In subsequent studies by various investigators, the use of intravenous essential amino acids combined with either glucose or lipid emulsion resulted in improved weight, nutrition, and plasma amino acid concentrations, which was not observed when either oral essential amino acids or intravenous nonessential amino acids were used. 17-19 Nevertheless, these studies are still inconclusive because endogenous aberrations of serum protein measurements in ESRD patients make the measurement of nutritional status difficult in this patient population. II However, measurement of these parameters serially over time in individual patients would increase their reliability as an outcome measure. In this report, 81 patients were studied over a 24-month period. Fifty patients received IDPN for an average period of treatment of 9 months. The mean age of the patient groups was 59.8 years. The patients were 47% black, 42% white, and 11 % Hispanic, and there was no significant

IDPN AND ESRD SURVIVAL

difference in demographics between the treated and untreated groups (Tables 2 and 3). Patients were selected for treatment on the basis of an abnormal serum albumin and weight loss occurring over a period of 2 successive months. Associated gastrointestinal symptoms, such as anorexia, nausea, vomiting, and/or diarrhea, were present in all patients treated. In this study, the survivors had mean body weights of 154.3 ± 32 Ib compared with 140.6 ± 31 Ib in the nonsurviving patients. The initial mean body weights of the treated and untreated groups were 129.9 ± 30 Ib and 144.5 ± 35 Ib, respectively. The initial mean serum albumin level was 3.06 ± 0.56 g/dL in the treated group and 2.94 ± 0.42 g/dL in the untreated group. Even though this was a nonrandomized study and the analysis was designed after all the data were collected, we did not find any significant differences in the baseline data between the treated and untreated patients. Patients selected for the treatment group had serum albumin levels less than 3.5 g/dL with significant weight loss. It seems unlikely that this selection protocol could bias results in favor of treatment, but that it is more likely to bias the untreated group. Nevertheless, the results still demonstrated a better survival rate in the treated group. In a breakdown between the treated and untreated survivors and nonsurvivors (Tables 5 and 7), certain significant factors emerge. The initial body weights were lower on average in the treated or untreated nonsurvivors than in the survivor groups. In addition, the treated survivors had significant increases in mean body weight at 8 months (157.3 ± 40 Ib) and further increases at 12 months (168.7 ± 44 Ib). Patients who were untreated or who did not survive demonstrated little or no weight gains or, in actuality, continued weight loss suggesting that unabated malnutrition persisted despite efforts at increasing protein caloric intake. The diabetic patients showed trends similar to those of the total caseload, with increases in serum albumin and body weight at the eighth month of therapy (Table 6). In addition, treated diabetic patients showed a substantially greater weight gain than nontreated diabetics at 8 months (160.5 ± 50 Ib) and 12 months (184.3 ± 50 Ib)

815

compared with the untreated group (156.7 ± 35 lb and 158.7 ± 36 lb, respectively). The significant factors that appear to emerge from this study are the delay in the correction of both the serum albumin levels and the improvement in body weights with the use of any form of nutritional therapy. There generally was no evidence for any change in either parameter until the sixth month of therapy. Thus, one cannot expect to treat these patients for a period of 1 to 3, or even 4, months and expect to see improvements. This obviously has several implications. Is it likely that reversal of protein caloric malnutrition requires such a prolonged use o£ IDPN, or is this merely a result of gradual improvement in overall nutritional intake, irrespective of IDPN? The failure of untreated patients to show significant improvements in either serum albumin and body weight, regardless of outcome, and over a comparable period of time suggests that the IDPN did indeed playa role in the correction of these nutritional parameters. The statistically significant difference in outcome, by Cox analysis, for treated patients versus untreated patients seems to answer the correlate question that once treatment begins to correct the nutritional deficiencies, then enhanced survival can be expected. Whether such an outcome can be demonstrated with an equivalent use of oral supplementation over time is unlikely because of the multiple factors adversely affecting the gastrointestinal system in nutritionally depleted patients and their poor compliance in continuous use of these agents over a prolonged period of time. 20-22 The second serious implication of this longterm therapy endeavor relates to the economic impact on the overall cost of ESRD care. Reimbursement restrictions by the Health Care Financing Administration for IDPN therapy are extremely severe, making ready availability of this therapy for ESRD patients very difficult or, in fact, unrealistic. Therefore, renal physicians and facility directors will be less likely to prescribe this mode of therapy unless the uncertainty surrounding reimbursement is resolved. The results of this study, albeit retrospective, provide supporting evidence that IDPN has significant beneficial effects on the protein malnutrition deficiency in the chronic hemodialysis patient and improves survival with proper selection of patients.

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REFERENCES 1. Laird NM, Berkey CS, Lowrie EG: Modeling-Success or failure of dialysis therapy: The National Cooperative Dialysis Study. Kidney Int 23:SIOI-106, 1983 (suppl 13) 2. Lowrie EG, Teehan BP: Principles of prescribing dialysis therapy: Implementing recommendations from the National Cooperative Dialysis Study. Kidney Int 23:S113-122, 1983 (suppl 13) 3. Lowrie EG, Lew NL: Death risk in hemodialysis patients: The predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 15:458-482, 1990 4. Capelli JP, Kushner H, Camiscioli TC, Chen SM, Stuccio-White NM: Factors affecting survival of hemodialysis patients utilizing urea kinetic modeling: A critical appraisal of shortening dialysis times. Am J Nephrol 12:112-122, 1992 5. Richards V, Hobbs C, Murray T, Mullen J: Incidence and sequelae of malnutrition in chronic hemodialysis patients. Kidney Int 14:683, 1978 6. Bansal V, Popil S, Pickering J, Ing TS, Vertuno LL, Hano JE: Protein-caloric malnutrition and cutaneous energy in hemodialysis maintained patients. Am J Clin Nutr 33: 16081611,1980 7. Degoulet P, Legrain M, Reach L: Mortality risk factors in patients treated by chronic hemodialysis. Nephron 31: 103110,1982 8. Knorr A, Schutt-Aine R: IDPN. A therapy caught up in Medicare regulations. Contemp Dial Nephrol 12:21-22, 1991 9. Phillips ME, Havard J, Howard JP: Oral essential amino supplementation in patients in maintenance hemodialysis. Clin Nephrol 9:241-248, 1978 10. Hecking E, Kohler H, Zobel R, Lammel E-M, Mader H, Opferkuch W, Prellwitz W, Keirn HF, Muller D: Treatment with essential amino acids in patients on chronic hemodialysis: A double-blind crossover study. Am J CIin Nutr 31:18211826,1978

11. Wolfson M: Use of nutritional supplements in dialysis patients. Semin Dial 5:285-290, 1992 12. Jindal KK, Manuel A, Goldstein MB: Percent reduction in blood urea concentration during hemodialysis (PRU): A simple and accurate method of estimate KtjV urea. ASAIO Trans 33:286-288, 1987 13. Gotch FA, Keen ML: Care of the patient on hemodialysis, in Cogen MG, Garoway MR (eds): Introduction to Dialysis. New York, NY, Churchill Livingstone, 1985, pp 73100 14. Owen WF, Lew NL, Liu Y, Lowrie EG, Lazarus JM: The urea reduction ratio and serum albumin concentration as predictors of mortality in patients undergoing hemodialysis. N Eng! J Med 328:1001-1006,1993 15. Acchiardo S, Moore L, Cockrell S: Effect of essential amino acids on chronic hemodialysis patients. ASAIO Trans 28:608-614, 1982 16. Heidland A, Kult J: Long-term effects of essential amino acids supplementation in patients on regular hemodialysis treatments. CIin Nephrol 3:235-239, 1975 17. Guarnieri G, Faccini L, Lipartiti T, Ranieri F, Spangero F, Giuntini D, Toigo G, Dardi F, Berquier-Vidali F, Raimondi A: Simple methods for nutritional assessment in hemodialyzed patients. Am J CIin Nutr 33:1598-1607,1980 18. Piraino AJ, Firpo JJ, Powers DV: Prolonged hyperalimentation in catabolic chronic dialysis therapy patients. JPEN J Parenter Enteral Nutr 5:466-477, 1981 19. Cano N, Labastic-Coeyrehourcq J, Lacombe P, Stroumza P, DiCostanzo-Dufetel J, Durbec JP, Couchay-Lucas C, Cynober L: Peridialytic nutrition with lipids and amino acids in malnourished hemodialysis patients. Am J CIin Nutr 52:726-730, 1990 20. Wolfson M: Severe malnutrition: I. Semin Dial 6:361362, 1993 21. Golper T: Severe malnutrition: II. Semin Dial 6:362364, 1993 22. Gupta BK, Plotner E, Spinowitz BS, Charytan C: Severe malnutrition: IV. Semin Dial 6:366-367, 1993