Uraemic symptoms, nutritional status and renal function in pre-dialysis end-stage renal failure patients

Francisco Caravaca, Manuel Arrobas, José L. Pizarro and Emilio Sanchez-Casado

S. Nefrología, Hospital Universitario Infanta Cristina, Badajoz, Spain



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Deciding on the right moment to initiate dialysis and finding the best method to establish this critical stage of chronic renal failure are both controversial issues. This study attempted to address this subject by correlating a uraemic score with the most common clinical methods for assessing renal function in pre-dialysis chronic renal failure (end-stage renal disease, ESRD) patients.

Methods. The study group consisted of 201 non-selected ESRD patients. A uraemic score, composed of the uraemic symptoms, the subjective global assessment of nutritional status, serum albumin concentration, and protein catabolic rate normalized for ideal body weight, was taken as a clinical marker of uraemic toxicity. Correlations that best fit this uraemic score with creatinine clearance (Ccr), the arithmetic mean of Ccr, urea clearance (Ccr-Cu) and Kt/V urea were then investigated.

Results. Thirty-six per cent of patients had malnutrition. By multiple logistic regression analysis, the presence of comorbidity, Ccr-Cu and haematocrit were the best determinants of malnutrition. The correlation that best fit Ccr or Ccr-Cu with the uraemic score was a cubic curve (r=0.38, P<0.0001, and r=0.42, P<0.0001, respectively), in which an ascending inflection was observed when Ccr and Ccr-Cu fell below 12–13 and 10 ml/min, respectively. However, the relationship between Kt/V urea and the uraemic score was less predictable, especially in male patients.

Conclusion. Ccr or Ccr-Cu are reliable methods for establishing the degree of severity of chronic renal failure below which the development of symptoms and malnutrition are highly prevalent. In contrast, Kt/V urea may be a less sensitive and specific method for assessing the severity of uraemia in ESRD patients.

Keywords: chronic renal failure; creatinine clearance; Kt/V urea; nutritional status; pre-dialysis



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Deciding on the right moment to start dialysis is an area subject to much controversy. Symptoms associated with terminal uraemia are unspecific, making it difficult to decide when to start dialysis. However, delaying dialysis treatment until patients present with severe complications secondary to terminal uraemia may increase morbidity and mortality, and the cost of treatment [13]. Thus, the key questions are how to estimate detrimental effects of terminal uraemia before patients develop severe complications, and at which degree of renal insufficiency severity do these detrimental effects become more evident?

In recent years, the idea that severity of azotemia should be evaluated by its potential detrimental effect on nutritional status in pre-dialysis chronic renal failure (end-stage renal disease, ESRD) patients has gained much support [47]. While these studies focused on the relationship between protein catabolic rate and renal function, it is less well known to what extent a reduction in dietary protein intake might provoke significant alterations in the nutritional status of these patients.

Based on the results of the adequacy parameters in peritoneal dialysis patients, a weekly renal Kt/V urea value of <2 has been proposed as a criterion for initiating dialysis treatment [810]. However, it is unclear whether a given value of renal Kt/V urea equates to a similar value of Kt/V urea provided by peritoneal dialysis or haemodialysis. Moreover, there is little known about the use of Kt/V urea as a method to establish the severity of uraemia in pre-dialysis end-stage renal failure patients.

The present cross-sectional study attempted to provide further information about these controversial issues, with the hope of facilitating future prospective studies on this subject. A uraemic score was composed of uraemic symptoms, the subjective global assessment of nutritional status, serum albumin and protein catabolic rate (protein of non-protein nitrogen appearance, PNPNA), and was correlated with the most common clinical methods for assessing renal function (creatinine clearance, the arithmetic mean of the creatinine and urea clearances, and Kt/V urea). The relationship between the uraemic score and renal function was weighed according to gender, age, the presence of comorbid conditions and the severity of anaemia.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The study group consisted of 201 patients (102 females and 99 males). Their mean age was 63±13 years, ranging from 16 to 84 years. There was no selection criterion. Included in the study were patients who were referred to our pre-dialysis consult from October 1996 to November 1999.

The aetiology of renal failure included: unknown origin (27), primary glomerulonephritis (38), diabetic nephropathy (51), chronic interstitial nephritis (42), ischaemic nephropathy (25) and adult polycystic kidney disease (18).

The patients were referred either by nephrologists or other medical specialists. In view of the severity of renal failure, many of these patients were considered as late referrals. None were on protein-restricted diets.

Definition of the uraemic score
A score of potential uraemic symptoms and a subjective global assessment of nutritional status were obtained in each patient by using questionnaires and physical examination.

Patients were asked specifically about the presence or absence of anorexia, nausea or vomiting, decreased physical activity, oedema, dyspnea or ortopnea, pruritus, bone pain, weakness, echimosis and/or epistaxis, muscle cramps, restless legs, diurnal somnolence, nocturnal insomnia, myoclonias, uncontrolled hypertension and cold intolerance. The presence or absence of each of these symptoms received the value 1 or 0, respectively. According to the sum of symptoms, a new partial score, which would eventually be utilized as a part of the global uraemic score, was obtained as follows: 0–4 symptoms (value 0); 5–9 symptoms (value 1), and >9 symptoms (value 2).

The subjective global assessment was determined by the method described by Detsky et al. [11]. The history of body weight changes, modifications in the diet, the presence of anorexia, nausea, or vomiting, loss of subcutaneous fat, muscle wasting, and the presence of oedema, composed the items that were evaluated and scored according to their severity.

On the basis of a subjective weighing of data, patients were classified as having no malnutrition (value 0), mild-moderate malnutrition (value 1) or severe malnutrition (value 2).

Serum albumin levels were determined by nephelometry. The severity of hypoalbuminemia was scored as follows: serum albumin >4 g/dl (value 0), serum albumin between 3 and 4 g/dl (value 1) and serum albumin <3 g/dl (value 2).

Using 24 h urine collections, total urea excretion and urea nitrogen generation rate were determined and utilized to calculate the protein of non-protein nitrogen appearance (PNPNA) according to the combined formulas of Cottini et al. and Maronni et al., as described by Bergström et al. [12]. Total PNPNA was normalized for ideal body weight. A PNPNA value >0.9 g/kg/day received the value 0, PNPNA between 0.6 and 0.9 g/kg/day received the value 1, and PNPNA <0.6 g/kg/day received the value 2.

The global uraemic score was composed of the sum of each of these four partial scores, and ranged from 0 to 8.

Determination of renal function
Patients were carefully instructed to collect their urine for a period of 24 h. The concentrations of urea, creatinine and total proteins were determined from samples taken from the total volume of urine. Determinations of serum urea and creatinine (Hitachi, Boehringer, Germany) were used to calculate creatinine (Ccr) and urea clearance (Cu) using conventional formulas. A more accurate approximation of glomerular filtration rate (GFR) was estimated by summing Ccr and Cu, and dividing by two (Ccr-Cu). These clearances were corrected for a standard body surface area of 1.73 m2.

Kt/V urea was calculated from the division of Cu (l/day) by the urea distribution volume, which was estimated using the formula of Watson et al. [13]. The result was expressed as weekly Kt/V urea.

Other clinical and biochemical determinations
In order to add more objectivity to the clinical exploration and to validate the results obtained by the subjective global assessment, the following anthropometric indices were measured: Body mass index (BMI, kg/m2), mid-arm circumference (MAC), triceps skin fold thickness (TSF) and mid-arm muscle circumference (MAMC=MAC-3.14x TSF). The results were expressed as percentiles of a healthy Spanish reference population [14,15]. The estimation of ideal body weight was based on the published concept of healthy body weight [16], meaning the ideal body weight for a given height, which is 24 kg/m2 for males and 23 kg/m2 for females.

Using 24 h total creatinine excretion, lean body mass was calculated by the formula of Forbes [18], correcting the result for the estimated extra-renal creatinine degradation [17].

A history of comorbid conditions that may potentially affect nutritional status (inflammatory disease, chronic heart failure, diabetes, etc.) was included in the analysis of the data.

Other biochemical determinations included serum transferrin (nephelometry), total cholesterol (Hitachi) and serum bicarbonate (IL-1306 gas analyser, Instrumental Laboratory, Milan). Serum C reactive protein levels (nephelometry) were determined in 61 patients.

Study design
Data obtained were from these patients during their first visit. They were cross-sectionally studied before treatment with dialysis or erythropoietin. Both the prevalence and determinants of malnutrition were investigated.

In order to establish the best determinants of malnutrition severity (dichotomous variable), a multiple logistic regression analysis was used, and included the following independent variables: age, gender, having at least one comorbid condition, Ccr-Cu, Kt/V urea, haematocrit (as a continuous variable), serum bicarbonate, and proteinuria.

Ccr was correlated with Kt/V urea, and potential determinants for discrepancies between these two parameters were investigated.

Finally, the correlations that best fit the global uraemic score, with each of the methods for evaluating renal function, were investigated. Partial correlations according to patient sex, age (older or younger than 65 years), the presence of at least one comorbid condition, and the severity of anaemia (haematocrit >30, 25–30 or <25%) were also examined.

Statistical analysis
Data are presented as means±SD, with a P-value of <0.05 taken to indicate statistical significance. Differences between the means of continuous variables were analysed using unpaired t-tests (two tailed). The Mann–Whitney test was used when two independent continuous variables with no normal distribution were compared.

The equation that best fit the relationship between the clinical methods for assessing renal function (serum creatinine, Ccr, Ccr-Cu and Kt/V urea) and the uraemic score was established by curve estimation analysis.

Multiple logistic regression analysis (forward conditional) was used to determine independent associations between one dichotomous dependent variable and more than two independent continuous or dichotomous variables.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Malnutrition in pre-dialysis end-stage renal failure patients
At the time of the study, none of the patients had severe complications due to terminal uraemia (pulmonary oedema, pericarditis, encephalopathy, severe hyperkaliemia or serum bicarbonate <12 mmol/l). More than half (102) had at least one major comorbid condition, which could potentially influence their nutritional status. Sixty-five patients had diabetes mellitus, 14 patients had chronic infectious or inflammatory disease, 12 had congestive heart failure, six had malignancy, four had chronic pulmonary obstructive disease, and one had liver cirrhosis. Fifty-five patients (27%) had at least one demonstrated atherosclerotic complication (coronary, central nervous system or peripheral). Sixty-one patients had nephrotic proteinuria.

According to the subjective global assessment, 128 (64%) patients had no malnutrition, 62 (31%) had mild-moderate malnutrition and 11 (5%) had severe malnutrition.

The clinical and biochemical characteristics for each nutritional status subgroup are summarized in Table 1Go. The mean percentile of the TSF thickness and MAMC were significantly greater in patients without malnutrition than in those with mild-moderate or severe malnutrition. Lean body mass, expressed as percentage of ideal body weight, was significantly larger in patients without malnutrition than that in patients with mild-moderate or severe malnutrition. PNPNA, corrected for ideal body weight, serum albumin and transferrin were also significantly greater in patients without malnutrition than in the two subgroups with malnutrition. There were no differences in total serum cholesterol, serum bicarbonate or total urinary protein excretion among the subgroups. The mean serum C reactive protein levels in the no-malnutrition subgroup were significantly less than those in the subgroup with mild-moderate malnutrition.


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Table 1. Clinical and biochemical characteristics for the subgroups according to the nutritional status established through the subjective global assessment

 
By multiple logistic regression analysis, the presence of comorbidity (odds ratio: 10.29; 95% CI: 4.73–22.37; P<0.0001), the Ccr-Cu (odds ratio: 0.96; 95% CI: 0.98–0.94; P=0.0015), and although less strong, the level of haematocrit (odds ratio: 0.91; 95% CI: 0.85–0.98; P=0.014), were the best determinants for the presence of or any degree of malnutrition.

Kt/V urea versus Ccr, Cu and Ccr-Cu
Kt/V urea and Ccr were significantly correlated (r=0.76, P<0.0001). However, at any given Ccr >10 ml/min, Kt/V urea was greater in female than in male patients. In patients with Ccr between 10 and 15 ml/min, Kt/V urea was significantly higher in female than in male patients (1.96±0.42 vs 1.65± 0.32, P=0.0001). This difference was weaker and not statistically significant when Ccr was between 15 and 20 ml/min (2.39±0.56 vs 2.13±0.44, P=0.093).

Ccr and Cu were significantly correlated (r=0.79), and there were no differences in intercepts or slopes of the partial regression lines for male and female patients.

In patients with a Cu 1.73 m2 <5 ml/min, the mean Kt/V urea was significantly greater in female than in male patients (1.31±0.25 vs 1.09±0.19, P=0.001). This difference was even greater when Cu 1.73 m2 was between 5 and 10 ml/min (2.22±0.41 vs 1.83±0.38; P<0.0001). These data suggest that when Kt/V urea is compared with clearances corrected for a standard body surface area, the discrepancies between patient sex are due to the utilization of the urea distribution of volume.

Relationship between PNPNA and renal function
As would be expected, Kt/V urea and PNPNA corrected for ideal body weight were significantly correlated. The relationship which best fit both parameters was a quadratic regression curve (r=0.53, P<0.0001). However, at any given Kt/V urea between 1.5 and 2.5, PNPNA corrected for ideal body weight was higher in male than in female patients (Figure 1Go).



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Fig. 1. Correlation between protein catabolic rate corrected for ideal body weight (PNPNA) and Kt/V urea. Individual male (closed circles, solid curve) and female patients (open circles, dotted curve) can be identified in the plot. r=0.47 and 0.62 for male and female patients, respectively.

 
PNPNA corrected for ideal body weight and Ccr-Cu were significantly correlated. The relationship which best fit both parameters was a linear regression line (r=0.51, P<0.0001), whose partial intercepts and slopes for male and female patients were very similar (Figure 2Go).



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Fig. 2. Correlation between protein catabolic rate corrected for ideal body weight (PNPNA) and the arithmetic mean of creatinine and urea clearances corrected for 1.73 m2 (Ccr-Cu). Individual male (closed circles, solid curve) and female patients (open circles, dotted curve) can be identified in the plot. r=0.51 and 0.53 for male and female patients, respectively.

 

Relationship between the methods for assessing renal function and the uraemic score
Serum creatinine did not correlate with the uraemic score (r=0.028). The correlation which best fit Ccr and Ccr-Cu and the uraemic score was a cubic regression curve. As displayed in Figure 3Go, an ascending inflection was visible when Ccr-Cu fell below 10 ml/min. This inflection was also evident when Ccr fell below 12–13 ml/min.



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Fig. 3. Correlation between the uraemic score and the arithmetic mean of the creatinine and urea clearances (Ccr-Cu) corrected for 1.73 m2 body surface area (BSA). Individual male (closed circles, discontinuous line) and female patients (open circles, dotted line) can be identified in the plot. The solid curve represents the regression curve for the whole group. y=7.36-0.95x+0.033x2-0.0010x3. r=0.42; P<0.0001.

 
The correlation which best fit Kt/V urea and the global uraemic score was also a cubic regression curve (r=0.37, P<0.0001). However, in female patients the shape of the curve was similar to the regression curve that fit Ccr and Ccr-Cu with the uraemic score, and in male patients the partial regression curve was unusual, displaying a biphasic shape and wider dispersion of data, making it impossible to reasonably predict the relationship between renal function and the uraemic score.

The mean uraemic score of 60 patients who had a Kt/V urea between 1.5 and 2 was substantially higher in female than in male patients (2.30±1.49 vs 1.61±1.30, P=0.05; Mann–Whitney test). However, there were no differences in the mean uraemic scores of the 60 male and 54 female patients who had Ccr-Cu between 5 and 10 ml/min (2.48±1.40 vs 2.66±1.57, not significant).

The partial regression curve from patients with at least one comorbid condition showed a marked increase in the uraemic score when the Ccr-Cu value fell below 20 ml/min. The 61 patients with nephrotic proteinuria showed a similar increase in the uraemic score but this was less evident in the non-nephrotic patients. The unique difference was an ~6% increase in the uraemic score at Ccr-Cu levels between 10 and 20 ml/min. The relationship between the uraemic score and Ccr-Cu did not differ substantially in aging patients (>65 years) compared with younger patients. In contrast, the severity of anaemia affected the relationship between the uraemic score and Ccr-Cu. When the Ccr-Cu value was >10 ml/min, patients with a haematocrit <25% had higher uraemic scores than patients with a less severe anaemia. Nevertheless, the uraemic score in the three subgroups increased sharply when Ccr-Cu fell below 10 ml/min (Figure 4Go).



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Fig. 4. Correlation between the uraemic score and the arithmetic mean of the creatinine and urea clearances (Ccr-Cu) corrected for 1.73 m2 BSA. Individual patients with haematocrits <25% (closed triangles, solid line), with haematocrits between 25 and 30% (closed circles, discontinuous line), or with haematocrits >30% (open circles, dotted line) can be identified in the plot.

 



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The uraemic score in the present study was composed equally of the potential uraemic symptoms and the subjective global assessment of nutritional status. Along with these subjective data, objective parameters which have been shown to correlate with the severity of renal failure or with morbidity-mortality among these patients, including protein catabolic rate and serum albumin concentrations, were also included into the score.

The main goals of dialysis treatment are precisely to avoid the development of these signs and symptoms. Therefore, their overt presence in pre-dialysis end-stage renal failure patients may present a reasonable indication that dialysis should be initiated.

As in any other cross-sectional study, some uncertainties may cloud the interpretation of the results. Perhaps one of the most important uncertainties in the present study was the time duration that patients were exposed to the severity of renal insufficiency for. The clinical consequences of terminal chronic uraemia can take a variable amount of time until they are fully manifested.

The inclusion of serum albumin in the uraemic score may be subject to controversy. In addition to malnutrition, nephrotic syndrome and inflammation may decrease serum albumin further [19]. Nevertheless, due to the semiquantitative weight of serum albumin in its contribution to the total uraemic score, nephrotic proteinuria did not appear to influence the results significantly (6% increase in the uraemic score of patients with nephrotic proteinuria). Furthermore, proteinuria (as a continuous variable) did not arise as a predictor of the uraemic score in the multiple regression analysis. In agreement with a previous study [20], serum C reactive protein levels were lower in patients with no malnutrition.

The correlation that best fit the uraemic score and Ccr or Ccr-Cu was represented by a cubic curve in which an ascending inflection was evident when Ccr and Ccr-Cu fell below 13 ml/min and 10 ml/min/ 1.73 m2, respectively. Interestingly, these relationships were similar regardless of patient sex or age. Furthermore, although comorbid conditions and the severity of anaemia contributed to the presence of more severe symptoms, the partial regression curves maintained the ascending inflection when Ccr or Ccr-Cu fell below the above-mentioned critical values.

In agreement with the guidelines of the Canadian Society of Nephrology for the initiation of dialysis [21], the results from the present study suggest that Ccr or Ccr-Cu are reliable methods for predicting the development of symptoms and malnutrition due to terminal uraemia, irrespective of the patient characteristics.

On the contrary, serum creatinine did not correlate with the uraemic score, and the relationship between the uraemic score and Kt/V urea was less predictable, primarily in male patients.

Kt/V urea is largely dependent upon V (urea distribution volume), which probably causes the discrepancies between Kt/V urea and other clearances corrected for a standard body surface area. This relationship may explain potential errors in the interpretation of Kt/V urea. For instance, underweight malnourished patients usually have a Kt/V urea which tends to overestimate Ccr corrected for 1.73 m2. On the contrary, a Kt/V urea value <2 is the rule in male asymptomatic well nourished patients with a Ccr between 10 and 20 ml/min/1.73 m2. Moreover, because Kt/V urea and protein catabolic rate corrected for the actual body weight are both strongly dependent on body weight, a potential coupled error may occur when both parameters are interpreted in patients with established malnutrition. Due to these facts, it is necessary to consider certain exceptions in order to interpret Kt/V urea correctly. These exceptions, which have been clearly detailed in the Dialysis Outcomes Quality Initiative guidelines [8], make Kt/V urea less predictable, as was demonstrated in the present study. The Kt/V urea is therefore less recommended for generalized use as a marker of renal function, at least in pre-dialysis chronic renal failure patients.

In the present study, the prevalence of malnutrition determined by the subjective global assessment was similar to that described in pre-dialysis [20], as well as in dialysis patients [22,23]. This study confirms that, together with the presence of comorbid conditions and the severity of the anaemia, the degree of severity of renal insufficiency in the pre-dialysis stage not only decreases protein catabolic rate, but is also a determinant of the presence of established malnutrition. Even after considering comorbidity and anaemia severity, the wide range of uraemic scores among patients with Ccr-Cu values <10 ml/min was noteworthy. A hypothetical explanation may be the time that patients had been exposed to severe renal insufficiency.

In most ESRD patients starting dialysis, nutritional status improves and nearly all uraemic symptoms vanish within a few weeks. This occurs despite the fact that artificial renal function improves to a Ccr-Cu of 10–12 ml/min at best. Thus, it appears that small variations around a certain level of uraemic toxin clearance marks the clinical tolerability of advanced uraemia. The mathematical relationship between the uraemic score and renal function observed in the present study supports this hypothesis further. Nevertheless, the flat relationship between the uraemic score and renal function in patients with Ccr-Cu between 10 and 20 ml/min should not be interpreted as a lack of deterioration at this stage of renal insufficiency. It is likely that deterioration could be better demonstrated if patients were compared with a healthy control group or with other uraemic patients with superior renal function, as was shown recently in the Modification of Diet in Renal Disease (MDRD) study [5,24]. Furthermore, pre-dialysis patients with renal function between 10 and 20 ml/min (Ccr-Cu) may exhibit less perceivable deterioration of the nutritional state, as was demonstrated in the slow progressive deterioration of nutritional status in patients on chronic dialysis [25]. This was difficult to demonstrate in short-term or in cross-sectional studies.

One subject of concern that this study raises is the better clinical tolerance of Kt/V urea values <2 in male compared with female patients. Although it can be argued that Kt/V urea provided by residual renal function is equal to that provided by peritoneal dialysis, this finding should warn against the more detrimental effects of underdialysis (assessed by Kt/V urea) in female compared with male patients. In this regard, female patients on peritoneal dialysis have higher tendencies towards anorexia, muscle wasting and hypoalbuminaemia than male patients [26]. Moreover, females also develop lower serum albumin concentrations during haemodialysis [27]. At present, there are no satisfactory explanations for these observations.

In conclusion, the relationship between the potential detrimental effects of uraemia with renal function in pre-dialysis renal failure patients is not linear, and is strongly influenced by comorbidity and the severity of anaemia. Ccr-Cu, corrected for a standard body surface area, appears to be a reliable method for establishing the severity of chronic renal insufficiency. Nephrologists should be aware that potential uraemic symptoms and malnutrition become sharply more intense when the renal function, determined by Ccr-Cu values, falls below 10 ml/min, irrespective of patient age or sex.



   Notes
 
Correspondence and offprint requests to: F. Caravaca, S. Nefrología, Hospital Infanta Cristina, E-06080 Badajoz, Spain. Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 5. 4.00
Revision received 16. 8.00.