Urea to creatinine ratio: a forgotten marker of poor nutritional state in patients undergoing hemodialysis treatment

Abstract

Background: Malnutrition is common in subjects undergoing hemodialysis and is associated with increased morbidity and mortality. Studies investigating factors associated with malnutrition and effect of various interventions to treat these patients are needed. We aimed to screen older and young patients undergoing chronic hemodialysis, for malnutrition, and seek its association with clinical factors including anxiety and depression and laboratory variables including urea/creatinine ratio (UCR).

Methods: Duration of hemodialysis treatment, medications taken, anthropometric measurements and routine laboratory results were recorded. Mini nutritional assessment and Beck anxiety and Beck depression inventories were applied. Study variables between subjects with malnutrition, malnutrition risk and normal nutritional states were compared. Older and younger patients were also compared regarding malnutrition and laboratory results. Linear regression analysis was performed to seek independent factors associated with malnutrition score.

Results: Clinical and laboratory data except for UCR were found to be similar among young and older patients. UCR increased, while albumin, body mass index and weight circumference decreased along with worse nutritional state. Low albumin level, body mass index and UCR and higher hemoglobin level and depression score were independent factors associated with malnutrition.

Conclusion: In addition to routinely used markers of malnutrition UCR may provide additional information regarding malnutrition in this population.

• Anxiety
• depression
• elderly
• hemodialysis
• malnutrition
• urea/creatinine ratio

Introduction

After the utilization of renal replacement treatment (RRT) modalities, older adults constitute an important proportion of the end stage renal disease (ESRD) population [1,2]. While obesity is a risk factor for ESRD, the rate of undernutrition is both rather high and associated with increased morbidity and mortality in patients undergoing RRT [3]. Both hemodialysis (HD) and peritoneal dialysis (PD) are associated with increased energy and protein needs [4]. Useful laboratory markers in the screening of malnutrition in different populations are scarce and mostly non-specific. Studies investigating factors associated with malnutrition and effect of various therapeutic interventions in patients with ESRD in different populations are needed. Although mini-nutritional assessment (MNA) is the most commonly recommended tool for older outpatient adults [5], studies utilizing MNA in patients undergoing HD, many of whom are older community-dwelling adults, are scarce.

In this study, we aimed to assess the utility of urea/creatinine ratio (UCR) in addition to routine laboratory tests in the diagnosis of malnutrition with commonly used markers in elderly and younger patients undergoing hemodialysis treatment. We also aimed to assess the effect of anxiety and depression on nutritional state.

Methods

This cross-sectional and observational study took place in a hemodialysis unit of a state hospital and another private hemodialysis center in Bursa, Turkey. Subjects undergoing HD for at least 1 month were enrolled to this study. Patients who were ≥65 years old were included in the elderly group and those <65 years old were included in the younger group. All of the subjects underwent HD treatment 3 times a week with a low-fluxpolysulfone hollow-fiber dialyzer (F10; Fresenius Medical Care, Bad Hamburg, Germany). Blood flow rate and dialysate flow rates were 200–350 and 500 ml/min, respectively. Subjects with acute kidney injury, malignancy and acute conditions potentially affecting nutritional state like infections with fever were excluded. The patients provided informed consent. The study was approved by the local ethics committee of Sevket Yilmaz Training and Research hospital and was conducted according to the principles of the Declaration of Helsinki.

Age, HD duration and medications of all of the subjects were recorded. Patients’ waist, arm and calf circumferences; weights and heights were measured after dialysis sessions. Body mass index (BMI) was calculated as weight (kg) divided by the height squared (m²). Routine laboratory results obtained before HD sessions were recorded. The Kt/V (K: dialyzer clearance of urea, t: dialysis time and V: distribution volume of urea) ratio was used as an index of HD treatment adequacy. A Kt/V value of ≥1.3 was considered to indicate adequate HD treatment [4]. MNA was applied to determine nutritional status. Beck anxiety inventory (BAI) and Beck depression inventory (BDI) were used to define anxious and depressive patients, respectively [6,7]. Cutoff values for depression and anxiety were accepted as 17 and 21, respectively. Patients were defined as having malnutrition if they had lower than 17 points, malnutrition risk (MR) if they had 17–23.5 points, and normal nutritional state (NNS) if they had 24 points or more in MNA test [8].

Statistical analysis

Normality of the distribution of the data was determined using the Kolmogorov–Smirnov test. Categorical data were expressed as percentages and continuous variables as means ± SDs or medians and interquartile ranges as needed. Age groups were compared using chi-square for categorical variables and with the Student t-test or Mann–Withney U-test for continuous variables. Agreement between hypoalbuminemia, low BMI and malnutrition according to MNA test was analyzed with Kappa test. Nutritional state groups were compared with chi-squared test for categorical variables and ANOVA or Kruskal–Wallis tests for continuous variables as needed. The correlation between MNA total score and age, HD duration, number of medications, anxiety score, depression score, BMI, waist circumference, albumin, hemoglobin, C reactive protein and UCR were sought using linear regression analysis. A two-sided p value < 0.05 was used to define statistical significance.

Results

Eighty patients were included in this study. The mean age was 55.8 ± 14.3 years. Female gender rate was 58.8%. Diabetes mellitus was present in 18.8% of the patients. Creatinine was significantly lower and UCR was higher, while urea tended to be lower in elderly group. Other clinical and laboratory data were similar among younger and elderly groups (Table 1). Nineteen patients’ albumin levels were <3.5 g/dl and 10 patients’ BMI were <20 kg/m². When these two criteria were combined, only five patients were classified as having protein energy wasting. According to MNA test, rate of malnutrition and malnutrition risk were 10% and 32.5%, respectively. While hypoalbuminemia had a weak level of agreement with a BMI <20 kg/m² (Kappa 0.21, p = 0.04), it had a stronger agreement with malnutrition according to MNA test (Kappa 0.44, p < 0.001). When the patients were compared according to their nutritional state groups, UCR and depression and anxiety scores and rates increased while albumin, creatinine, BMI and WC decreased in worse nutritional state groups (Table 2). Frequency of anemia was similar among patients with malnutrition and those without malnutrition. While Kt/V was similar among subjects with NNS and MR, it was significantly lower in subjects with malnutrition compared to subjects with NNS.

Table 1. Comparison of age groups.

	<65 years, n = 57	≥65 years, n = 23	p
Gender (% females)	59.6	56.5	0.8
Age	52 (17)	70 (9)	<0.001
Malnutrition (%)	8.8	13	0.68
Malnutrition risk (%)	35.1	26.1
Normal nutritional state (%)	56.1	60.9
MNA-screening score	13 (4)	12 (4)	0.5
MNA-total score	24 (3.5)	24 (5.5)	0.97
Diabetes mellitus (%)	15.8	26.1	0.29
Depression (%)	22.8	30.4	0.48
Depression score	10 (11.5)	10 (13)	0.8
Antidepressant use* (%)	38.5	28.6	1
Anxiety (%)	14	13	1
Anxiety score	8 (11.5)	9 (12)	0.6
HD duration (years)	4.75 (7.75)	4 (7.5)	0.1
Medication number	6 (2.5)	5 (4)	0.3
Waist circumference (cm)	96.3 ± 15.9	98.4 ± 17.9	0.5
BMI (kg/m^2)	25.1 ± 4.5	25.1 ± 3.2	0.98
Albumin (g/dl)	3.8 ± 0.5	3.6 ± 0.6	0.09
C reactive protein (mg/l)	1.2 (3.46)	0.9 (1.56)	0.8
Urea (mg/dl)	115 (84.1)	119 (52)	0.5
Creatinine (mg/dl)	8 ± 2.1	6.7 ± 2.1	0.02
UCR	14.3 ± 6	18.6 ± 7.1	0.007
Kt/V ratio	1.5 (0.63)	1.4 (0.5)	0.2
Hemoglobin (g/dl)	11.6 (1.6)	10.5 (2.2)	0.001
Phosphorus (mg/dl)	4.9 ± 1.3	4.4 ± 1.7	0.1
Ferritin (ng/ml)	1043 (1399)	1114 (1467)	0.5

HD, hemodialysis; BMI, body mass index; UCR, urea/creatinine ratio.

*Antidepressant use among patients with depression according to Beck depression scores.

Table 2. Comparison of nutritional state groups.

	Malnutrition (n = 8)	MR (n = 26)	NND (n = 46)	p
Age	57.3 ± 21.7	54.5 ± 14.8	55.8 ± 12.9	0.87
Gender (%females)	62.5	73.1	50	0.16
Depressive (%)	62.5	34.6	13	0.005
Depression score	17 (14)	14.5 (15.5)	9 (9.25)	0.003
Antidepressant use* (%)	20	44.4	33.3	0.65
Anxiety (%)	25	23.1	6.5	0.09
Anxiety score	14 (18.75)	11 (11.75)	6 (10)	0.004
Diabetes mellitus (%)	12.5	26.9	15.2	0.4
HD duration (years)	1.5 (5.125)	4 (9.5)	4.75 (6.25)	0.18
Medication number	5.5 (2.75)	7 (2.75)	5.5 (3)	0.35
Waist circumference (cm)	83.5 (23)	93 (18.75)	103 (14.25)	0.001
BMI (kg/m^2)	20.5 ± 2.3	24.1 ± 4.1	26.5 ± 3.6	<0.001
Albumin (g/dl)	2.9 ± 0.7	3.6 ± 0.4	3.9 ± .4	<0.001
C reactive protein (mg/l)	5.8 ± 7.7	4.8 ± 10.1	4.9 ± 9.8	0.97
Urea (mg/dl)	124.6 ± 34.5	119.8 ± 49.7	110 ± 51.5	0.6
Creatinine (mg/dl)	6.8 ± 1.6	7 ± 1.9	8.1 ± 2.2	0.045
UCR	18.4 ± 3.5	17.3 ± 7.8	13.8 ± 5.7	0.013
Kt/V ratio	1.3 (0.3)	1.57 (0.6)	1.57 (0.6)	0.13†
Hemoglobin (g/dl)	11 ± 1.8	10.8 ± 1.6	11.2 ± 1.4	0.56
Anemia (%)‡	62.5	60	52.2	0.6
Phosphorus (mg/dl)	4 ± 1.7	4.9 ± 1.7	4.8 ± 1.1	0.28
Ferritin (ng/ml)	1405.5 (1472)	869 (1462.5)	1056 (1284)	0.77

HD, hemodialysis; BMI, body mass index; UCR, urea/creatinine ratio; MR, malnutrition risk; NNS, normal nutritional state.

*Antidepressant use among patients with depression according to Beck depression scores.

†No significant difference between MR and NNS groups, and a significant difference between malnutrition and NNS groups (p = 0.04).

‡A hemoglobin level of <11 g/dl for women and <12 g/dl for men.

15 of 76 patients were under antidepressant treatment. Mean MNA, anxiety, and depression scores, age, and HD duration were similar between subjects who were under antidepressant treatment and those who were not (Table 3). Only the rate of depression according to BDI was higher in subjects under antidepressant treatment. Although the frequency of depression was very high in patients with malnutrition, usage of antidepressant medications was very seldom.

Table 3. Comparison of subjects under and not under antidepressant treatment.

	Under ADT	Not under ADT	p
Age	57.1 ± 11.6	55.6 ± 15.2	0.72
Gender (%females)	66.7	59	0.59
Depression (%)	46.7	21.3	0.046
Depression score	14 (18)	9.5 (11)	0.1
Anxiety (%)	13.3	13.1	1
Anxiety score	11 (12)	8 (12)	0.56
HD duration (years)	1.5 (5.125)	4 (9.5)	0.48
MNA score	24.5 (6)	24 (3.4)	0.96

HD, hemodialysis; BMI, body mass index; ADT, antidepressant treatment; HT, hemodialysis treatment; MNA, mini nutritional assessment.

Linear regression analysis revealed lower albumin (t = 7.7, p < 0.001), BMI (t = 4.7, p < 0.001) and UCR (t = 1.9, p = 0.07); and higher hemoglobin (t = −2, p = 0.046) and depression score (t = −2.8, p = 0.007) as independent factors associated with malnutrition.

Discussion

In this study, we found high rates of malnutrition and malnutrition risk in older and younger subjects under HD. The rates were similar in both age groups. Our results also indicated UCR as a potential and independent marker in the screening of this population for malnutrition. We also detected a high rate of depression and anxiety especially in subjects with worse nutritional states, which seemed to be undertreated. In addition to classical risk factors for malnutrition, depression seemed to be an independent factor associated with it. Kt/V ratio as a marker of HD adequacy was lower in subjects with malnutrition than those with NNS.

The most commonly used laboratory analyses to screen for malnutrition are albumin and prealbumin. UCR is correlated with protein intake at all levels of renal function [9]. Theoretically, when creatinine production is diminished due to muscle loss, thus UCR would be higher at a given protein intake [9]. To our knowledge, UCR has not been directly assessed as a potential marker for malnutrition in hemodialysis patients. In one retrospective study, 23 patients who died within 90 days of initiating dialysis and 20 patients who survived >10 years under dialysis treatment were compared [10]. Although the authors did not report the association of UCR with malnutrition in this study, multivariate analysis showed that higher age and UCR were independently related to early death. In our study, creatinine levels were lower and although not statistically significant urea tended to be higher either in older subjects and patients with worse nutritional states. Because levels of creatinine is related to muscle mass, lower creatinine and higher UCR in worse nutritional states and advanced age may be associated with sarcopenia. Results of our study indicate that UCR may also be used as a beneficial marker to assess the presence of malnutrition.

While obesity and metabolic syndrome are well known risk factors for ESRD, undernutrition which is associated with acute complications is common in patients with CKD [3]. In these patients, inadequate food consumption is common as a result of uremic nausea and anorexia, restrictive diet lists, and abstinence from volume overload, while energy and protein needs are increased due to chronic inflammation, proteinuria, inter-current infections and nutrient loss by dialysis procedures, inadequate dialysis and membrane bio-incompatibility. While there are studies indicating protein restriction without protein malnutrition slows the progression of CKD [11,12], there are also prospective and randomized studies which did not show such benefit [13,14]. It is also reported that benefits of protein restriction may at least partially be the result of phosphorus restriction with these low-protein diets [15–17]. On the other hand, patients with CKD especially those on renal replacement therapy (RRT) are at increased risk for malnutrition which is the strongest risk factor in these patients for adverse outcomes including death [3]. A recently published 10-year follow-up cohort study in patients on hemodialysis assessing the predictive effect of albumin, C-reactive protein and carotid atherosclerosis on mortality indicated that hypoalbuminemia was the strongest independent risk factor [18]. Long-term follow-up data of the Modification of Diet in Renal Disease (MDRD) study showed that, compared to low protein intake (0.58 g/kg/day), very low protein intake (0.28 g/kg/day) was associated with faster progression of CKD and higher mortality rate [19]. In this study, both groups were given essential ketoacid and amino acid mixture. Current Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines recommend a protein intake of 0.6–0.75 g/kg/day in stage 1–4 CKD, 1.2 g/kg/day in hemodialysis patients and 1.2–1.3 g/kg/day in peritoneal dialysis patients [4]. However, in clinical practice many patients under RRT consume lower than recommended protein [3]. For instance, in the HEMO study, protein intake of the patients was 0.9 ± 0.41 g/kg on the hemodialysis days and 0.96 ± 0.43 g/kg on the other days [20].

Studies evaluating nutritional state in patients with ESRD generally used various tools like subjective global assessment and malnutrition-inflammation score. Although MNA is the most commonly recommended test to assess malnutrition in outpatient elderly [5], there is a lack of utilization of MNA test in ESRD population which include an important elderly proportion. To our knowledge, a few studies utilized MNA for the assessment of nutritional status in hemodialysis patients [21,22]. We found a high rate of malnutrition and malnutrition risk in this population with MNA test. Notably, many elderly patients with a normal BMI have malnutrition or malnutrition risk. We suggest that using a BMI <20 kg/m² for this population may give erroneous results and underestimate the rate of malnutrition. The stronger agreement between hypoalbuminemia and a low MNA score compared to a low BMI in our study supports this suggestion. Furthermore, using solely these criteria which does not assess recent weight loss and decrease in oral intake would result in overlooking of patients with MR.

A recent study performed in 12 hemodialysis centers in Brazil sought factors associated with malnutrition in these patients. They found an age over 60 years, low income, retirement and depression as independent factors associated with malnutrition [23]. However, regarding depression, rather than utilizing a validated scale, they asked the patients if they had depression or not. Some other studies regarding risk factors for malnutrition in hemodialysis patients did not assess the presence of depression [24–26].

The results of studies assessing the association between depression and malnutrition showed variable results [27–29]. These studies most commonly used BDI as screening tool for depression. In our study, the rate of undiagnosed depression was high especially in patients with malnutrition and malnutrition risk. Interestingly, only one-fifth of patients with depression and malnutrition have been on anti-depressant treatment. Both depression and overt kidney failure may lead to chronic anorexia, thus increase the risk of malnutrition. Many chronic conditions like heart failure and arthritis are associated with medical illness related depression [30]. The underlying medical illness may worsen the prognosis of depression and depression may influence remission of medical illnesses by decreasing motivation and compliance [31].

The Kt/V ratio was lower in the malnutrition group compared to NNS group. This finding possibly suggests that the accuracy of Kt/V ratio may be lower in patients with malnutrition. One would expect a worse nutritional state in case of HD inadequacy because of the suppressant effects of uremic state on appetite. However, Kt/V was not correlated with nutritional state in the regression analysis, indicating this may be an incidental finding.

The limitations of our study include the cross-sectional design and small sample size. Prospective studies assessing the role of UCR in the screening and follow-up of patients with malnutrition on RRT may be valuable. More studies are also needed to investigate the cost effectiveness of screening for and treating depression and its effect on nutritional state in these subjects.

Conclusions

We suggest that UCR may prove to be a beneficial marker in nutritional assessment in patients undergoing hemodialysis treatment. Depression seems to be common, underdiagnosed and associated with malnutrition in younger and elderly patients undergoing hemodialysis treatment.

Acknowledgements

We thank the dialysis center staff for their help in obtaining our data.

Declaration of interest

The authors report no declarations of interest.