Relationship Between Residual Kidney Function And Symptom Burden in Hemodialysis Patients

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Jessica H. Kong, et al

Abstract

Background: Residual kidney function (RKF) has been associated with improved solute clearance and survival in hemodialysis (HD) patients. However, whether RKF (Residual kidney function) impacts symptom burden in HD (hemodialysis) patients is unknown.

Aims: To determine the prevalence of RKF (Residual kidney function) in HD patients and to explore associations between higher levels of RKF (Residual kidney function) with symptom burden, as well as clinical and biochemical parameters. Methods: This is a single-center, retrospective, observational study. RKF was assessed as urea clearance (KRU) by interdialytic urine collection. Symptom burden was measured using the palliative care outcome scale renal questionnaire.

Results: A total of 90 maintenance HD (hemodialysis) patients was recruited; 31.9% had KRU ≥1 mL/min/1.73 m2. Patients with KRU ≥1 mL/min/1.73 m2 reported fewer symptoms (5.3+- 3.5 vs 7.7 +-3.8) (P = 0.011), including less shortness of breath (15% vs 55%) (P = 0.0013) and vomiting (0% vs 30%) (P = 0.0016). Higher RKF (Residual kidney function) was associated with lower β2-microglobulin (P < 0.0001), and lower serum potassium (P = 0.02), but no difference in phosphate, hemoglobin, C-reactive protein, or serum albumin.

Conclusion: Higher RKF was significantly associated with fewer symptoms, and lower serum β2-microglobulin and potassium, suggesting that strategies to preserve RKF (Residual kidney function) may be beneficial.

Keywords: residual kidney function, hemodialysis, uraemic symptom, β2-microglobulin, potassium

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Introduction

In hemodialysis (HD) patients, higher levels of residual kidney function (RKF) have been correlated with better outcomes, including improved survival, nutrition,1 anaemia2, and phosphate control.3 Despite this, in contrast to peritoneal dialysis, RKF (Residual kidney function) is not routinely monitored in most HD patients, so the effects of RKF (Residual kidney function) on the control of uremia in HD (hemodialysis) patients are frequently overlooked. In contrast to the intermittent nature of HD, RKF achieves continuous solute clearance and fluid removal, such that even low levels of RKF could have meaningful effects. HD dose is most commonly determined and monitored by the urea clearance of an individual treatment session, not taking into account RKF. Nonetheless, various methods such as standard Kt/V (StdKt/V)4 and equivalent renal urea clearance5 have been developed, aiming to integrate the dialysis clearance with RKF (Residual kidney function). The US Kidney Disease Outcomes Quality Initiative (KDOQI) guideline suggests that for HD patients with RKF of ≥2 mL/min/1.73 m2 urea clearance (KRU), the dose of HD (hemodialysis) may be reduced provided RKF is measured periodically to avoid inadequate dialysis.6

End-stage kidney disease (ESKD) is associated with reduced quality of life and a large symptom burden.7 While HD (hemodialysis) prolongs life in ESKD, the burden of uraemic symptoms remains high in these patients.8 Disappointingly, more intensive HD regimens do not necessarily improve the quality of life in HD patients.9 The high symptom burden in HD patients might be related to some extent to the poor removal of certain uraemic solutes by HD.10 Whereas HD efficiently removes low-molecular-weight uraemic toxins, RKF (Residual kidney function) is comparatively more efficient for larger molecular weight and protein-bound uraemic solutes, which are poorly removed by HD.10 Recently, there has been renewed interest in the role of RKF (Residual kidney function) in HD patients, and how RKF might be integrated into the care of HD (hemodialysis) patients. Little is known about the relationship between RKF (Residual kidney function) and symptom burden in HD patients.

The aim of this study was to determine the prevalence of RKF (Residual kidney function) in a cohort of HD (hemodialysis) patients, and to examine the associations of RKF with symptom burden and solute clearance, hypothesizing that higher levels of RKF (Residual kidney function) in HD patients will be associated with improvements of these parameters.

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Methods

This is a single-center, retrospective, observational study. Ethics approval was granted by The Austin Health Human Research Ethics Committee as a low-risk study (LNR/17/Austin/414).

Patients

We extracted medical record data from all HD (hemodialysis) patients aged >18 years treated under Austin Health from 1 October 2017 through 1 May 2018. All were clinically stable at the time of the study and were treated with high-flux membranes produced by Baxter (Revaclear and Polyflux, Deerfield, IL, U.S.A.).

Data collection

RKF was assessed by a timed interdialytic urine collection between the first and second dialysis sessions of the week. Patients with self-reported urine output of >200 mL over the interdialytic period were considered to have an RKF (Residual kidney function) value of 0 mL/min/1.73 m2. Patients who had a self-reported interdialytic urine output ≥200 mL but were unwilling or unable to perform a timed urine collection were excluded from the study.

Symptom burden was measured using the palliative care outcome scale symptom questionnaire modified for use in patients with renal failure (POS renal). Functional status was assessed with the Karnofsky performance score. The POS renal questionnaire includes 17 symptoms, each graded from 0 to 4 as absent (0), mild (1), moderate (2), severe (3), or overwhelming (4). A total symptom score was calculated by adding the graded score for each individual symptom (possible range = 0–68). Data were collected retrospectively using the most recently available completed questionnaire.

Demographic, clinical, and laboratory measures

Demographics and medication use were obtained from the electronic medical record. Comorbidities were assessed using the Charlson comorbidity index. Laboratory data were available from routine patient care. Dialysis information was obtained from the second dialysis session of the week of the RKF (Residual kidney function) assessment. Blood pressure (BP) measurements were performed before and after each dialysis session in a seated position.

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Total solute clearance and dialysis adequacy

Renal urea clearance (KRU) and creatinine clearances were calculated from timed urine collection and corrected for a body surface area of 1.73 m2 (Mosteller equation). Urine collections began at the end of the first dialysis session of the week until the commencement of the next session (approximately 43.5 h). Mean interdialytic urea and creatinine concentration was calculated using the mean of the pre-and post-dialytic plasma concentrations. Post-dialysis blood tests were performed using the slow pump method, in which the blood flow is reduced to 50–100 mL/min for 2 min while the dialysate flow is ceased, prior to taking the blood sample. Residual glomerular filtration rate (GFR) as mL/min/1.73 m2 was defined as the mean of urea and creatinine clearances, as per European Best Practice Guidelines.11

Total weekly dialysis clearances were determined by urea clearance, using the StdKt/V derived from Gotch and Leypoldt’s fixed volume equation as adapted by Daugirdas et al.,4 calculated by using an available online calculator (www.hdcn/calf/ley.htm). To allow summation of dialysis and native clearances the total weekly KRU was converted to a weekly renal StdKt/V. Total body water was determined by the Watson equation. The total (dialysis + renal) weekly StdKt/V was determined by adding the dialysis and renal StdKt/V value.

Statistical methods

Categorical variables were summarised as percentages. Continuous variables were reported as means with standard deviations (SD). Means were compared using a one-sample t-test. Baseline characteristics of participants were compared based on their KRU using Mann–Whitney test or Chi-squared test, as appropriate. Fisher exact test was used for categorical variables with n < 5 for one or more comparator groups. Pearson correlation analysis was used to model the association between measures of RKF(Residual kidney function) and continuous variables, including β2M, potassium, hemoglobin, C-reactive protein (CRP), time on renal replacement therapy, and a number of symptoms. Statistical analyses were performed using GraphPad InStat software, version 3.10. Graphs were generated using GraphPad Prism software, version 7.04, or Microsoft Excel 2016 MSO version (16.0.9330.2073) significance was defined as P ≤ 0.05 using two-tailed tests.

Results

Participant characteristics A total of 101 maintenance HD (hemodialysis) patients were screened, and 90 were included in the study; 11 non-anuric patients in the cohort were excluded from the study due to lack of timed urine collection for analysis (eight patients refused, three were unable to perform).

Baseline characteristics of the participants were stratified by KRU level <1 and ≥1 mL/min/1.73 m2, as described in Table 1. Of the 90 patients, 61.1% of patients were anuric, defined as a measured or self-reported urine output of less than 200 mL over the interdialytic period. The mean KRU was 0.91+-1.37 mL/min/1.73 m2. The mean GFR was 1.53+-2.16 mL/min/1.73 m2. Patients with higher levels of RKF(Residual kidney function) were younger (P = 0.042) and more likely to be male (P = 0.040) and Asian (P = 0.038). They also had a shorter duration of renal replacement therapy (P < 0.0001) and HD (hemodialysis) therapy (P < 0.0001). A higher proportion of patients with greater RKF (Residual kidney function) were on diuretic therapy, with 39.3% of patients with KRU ≥1 mL/min/1.73 m2 on diuretics compared to 9.7% in patients with KRU <1 mL/min/1.73 m2 (P = 0.0024).

table 1

Prevalence and trend of RKF (Residual kidney function)

The prevalence of RKF (Residual kidney function), expressed in percentages, is shown in Figure 1. Of the 90 patients, 31.1% of patients have KRU ≥1 mL/min/1.73 m2 and 17.8% of patients have KRU ≥2 mL/min/1.73 m2. The mean time on HD (hemodialysis) for patients with KRU <1 and ≥1 mL/min/1.73 m2 was 6.5 +-7.8 and 1.6 +- 1.7 years respectively. Longer duration of HD (hemodialysis) therapy significantly correlated with lower KRU levels (P < 0.0001) as shown in Figure 1B. All of the patients who had been on HD for 9 years or more (n = 13) were anuric (Table 2).

Clinical and biochemical correlations with RKF (Residual kidney function).

Table 2 compares dialysis parameters and biochemical data for participants, stratified according to the degree of RKF (Residual kidney function). The pre-dialysis and post-dialysis diastolic BP in patients with KRU ≥1 mL/min/1.73 m2 were significantly higher compared to patients with KRU <1 mL/min/1.73 m2, but there was no significant difference in systolic BP or pulse pressures between the two groups.

Higher KRU ≥1 mL/min/1.73 m2 was significantly associated with lower serum β2M levels (P < 0.0001) and lower serum potassium (P = 0.027). Haemoglobin, phosphate, albumin, parathyroid hormone, and CRP were not related to the KRU level. There was also no difference in erythropoietin requirements. By correlation analysis, higher KRU correlated with lower serum levels of β2M and potassium (Fig. 2A, B). These differences existed despite the fact that patients with low KRU <1 mL/min/1.73 m2 were managed with longer hours of HD (hemodialysis) and had a higher proportion of patients treated with haemodiafiltration (HDF). Further analysis of potassium parameters between the two groups found similar rates of hyperkalemia and use of low potassium dialysate.

The low KRU group was treated with slightly more intensive dialysis as indicated by longer treatment times (P = 0.049) and a higher dialysis weekly StdKt/V (2.46 +- 0.21 vs 2.30 +- 0.24; P = 0.0007) (Table 2). This difference was despite the fact that no policy was in place in our hospital at the time of the study to adjust the dialysis prescription according to RKF (Residual kidney function). However, when the residual renal clearance was added to the dialysis clearance, the total urea clearance as measured by total StdKt/V was significantly higher in the high KRU group (2.97 +- 0.42 vs 2.51 + 0.23) (P < 0.0001). Figure 2C illustrates the contribution of the RKF(Residual kidney function) (renal StdKt/V) to the total urea clearance in the study cohort, with the RKF contributing up to a maximum of 38% of the total StdKt/V.

table 2

Symptom burden

The symptom burden of the patient cohort is summarised in Table 3. Self-reported symptom questionnaires were completed by 53 patients in the low RKF (Residual kidney function) group and 26 patients in the high RKF group. Across the entire cohort, the most common symptom was weakness/lack of energy (72.7%). However, the pain was the symptom most commonly rated as severe or overwhelming (16.5%). Patients with KRU ≥1 mL/min/1.73 m2 reported fewer symptoms than patients with KRU <1 mL/min/1.73 m2 (5.3 +- 3.5 vs 7.7 +- 3.8, P = 0.014). Non-severe symptoms (score 1 or 2) were more common than severe symptoms (score 3 or 4) and accounted for the differences between the two groups. With respect to specific symptoms, vomiting, shortness of breath, poor appetite, and poor mobility were more common in patients with KRU <1 mL/min/1.73 m2 (Table 4). Fifteen of the 17 symptoms were numerically more common in the low RKF (Residual kidney function) group. Karnofsky performance scores were similar in the two groups (78.8 +- 14.5 vs 74.8 +- 13.3, P = 0.17) (Table 3).

table 3

table 4-1

table 4

A negative correlation was noted between KRU and the number of patient-reported symptoms (Fig. 3A) (r = −0.212, P = 0.05). There was also a trend to fewer symptoms with higher weekly standard Kt/V (renal plus dialysis) (Fig. 3C). However, interestingly there was no correlation between the number of symptoms and dialysis clearance of urea (spKt/V) (Fig. 3B). Higher levels of β2M correlated with a greater number of symptoms (Fig. 3D) (r = 0.234, P = 0.033). There were no significant correlations observed between the number of symptoms and age or dialysis vintage (Fig. 3E, F)

Discussion

This analysis of RKF (Residual kidney function) from a cohort study of maintenance HD (hemodialysis) patients demonstrates that there is a subgroup of HD patients with significant RKF, at a level that contributes meaningfully to their total solute clearance, including urea kinetics, middle molecule, and potassium homeostasis. In addition, we observed that ESKD patients on HD patients with higher levels of RKF have fewer uraemic symptoms.

While RKF has been associated with a better quality of life in peritoneal dialysis and HD (hemodialysis) patients,12,13 the relationship between RKF (Residual kidney function) and symptom burden in HD(hemodialysis) patients has not previously been studied. In the present study, we observed that HD (hemodialysis) patients with lower RKF (Residual kidney function) had a higher number of self-reported symptoms. The relationship between RKF and symptoms varied substantially between symptoms, for example, shortness of breath and vomiting were significantly more common among those with low RKF (Residual kidney function), while various other symptoms were not different between groups. Interestingly, while RKF (Residual kidney function) negatively correlated with the number of symptoms, there was no relationship between symptoms and the clearance of urea by HD (hemodialysis), measured by spKt/V. In addition, a relationship was noted between serum β2M and the number of symptoms, whereas there was no relationship between the number of symptoms and either age or the number of years of RRT. While such observational data are hypothesis-generating rather than conclusive, they suggest that the beneficial effect of RKF (Residual kidney function) in relieving the burden of uraemic symptoms extends beyond the clearance of low-molecular-weight solutes such as urea. A limitation of our study is that our observations regarding uraemic toxins were limited to urea, potassium, and β2-microglobulin. Importantly, however, RKF (Residual kidney function) contributes to the clearance of a broad range of uraemic toxins. For example, it was recently reported that even very low-level RKF (Residual kidney function) less than 1.5 mL/min, was associated with lower serum levels of a range of uraemic solutes, including hippurate, trimethylamine-N-oxide, and asymmetric dimethylarginine.14 In addition to the role of glomerular filtration, RKF is also reported to increase the clearance of secreted protein-bound solutes such as indoxyl sulfate, p-cresol sulfate, and homocysteine.15,16 Enhanced clearance of these uraemic solutes such as these by RKF may contribute clinical benefits in patients on dialysis. It is worth noting that while symptom burden was lower in the RKF group, on average these patients still reported the presence of more than five symptoms. Furthermore, on average patients reported one symptom as being severe or overwhelming with no significant difference between groups in the number of these severe symptoms. This high burden of symptoms in HD (hemodialysis) patients has been well documented by previous studies7,8 and indicates an ongoing need for better symptom management in these patients.

While RKF (Residual kidney function) has been reported to be preserved better with peritoneal dialysis compared with HD (hemodialysis), there is emerging evidence that a substantial proportion of HD patients retain significant degrees of RKF (Residual kidney function), and the use of high-flux biocompatible dialyzers may contribute to better preservation of RKF (Residual kidney function) in the modern era.12,17 Vilar et al. reported that 58.1% and 31% of 650 HD (hemodialysis) patients had a KRU ≥1 mL/min/1.73 m2 at 2 years and 5 years after HD (hemodialysis) initiation respectively.2 Consistent with this, the present study also found a subgroup of HD (hemodialysis) patients with significant levels of RKF – 31.1% of patients had KRU ≥1 mL/min/1.73 m2 and 17.8% of patients had KRU≥2 mL/min/1.73 m2. The prevalence of RKF in our patient cohort may be underestimated with the exclusion of nonanuric subjects who were unwilling or unable to perform a timed urine collection, whereas the anuric patients remained included in our analysis. In accordance with previous studies, our study also shows that a longer duration of HD therapy significantly correlates with lower RKF.2,17.

While our study was not powered to detect a difference in mortality, previous studies have found an association between RKF (Residual kidney function) and improved survival in HD(hemodialysis) patients.13,18,19 For example, in the Netherlands Cooperative Study on the Adequacy of Dialysis study of 740 incident HD patients, mortality was 56% lower with each 1.0 unit increase in renal urea StdKt/V per week over the median follow-up time of 1.7 years.12 The survival benefit conferred by RKF may be partly attributed to better clearance of solutes, including that of middle molecular weight uraemic toxins such as β2M, which are poorly cleared by HD.20 We confirmed that a higher level of RKF is significantly associated with lower serum β2M. In our cohort, this was despite the greater use of HDF in the low RKF group, which would have diluted the effect of RKF (Residual kidney function) on β2M that we observed. Our results are consistent with those reported in the study by Fry et al., where patients with KRU of 0.5–1 mL/min had significantly lower β2M levels compared to those with KRU <0.5 mL/min,20 suggestings that even low levels of RKF may contribute to substantial solute clearance.

An interesting finding in our study is that RKF (Residual kidney function) was significantly associated with lower serum potassium, which was observed despite no difference in dialysate potassium concentration between the two groups. The observation that patients with KRU≥1 mL/min/1.73 m2 had significantly lower serum potassium, suggests that even low levels of RKF may significantly contribute to overall potassium balance. The difference in serum potassium levels may also be partly attributed to the higher incidence of use of diuretics in patients with higher RKF levels, consistent with a study from the Dialysis Outcomes and Practice Patterns Study finding that HD (hemodialysis) patients on diuretics have a lower risk of hyperkalemia.21 One limitation of our analysis that should be addressed in future studies is that we did not directly measure urinary potassium excretion in HD (hemodialysis) patients.

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In contrast to previous studies, we did not observe any significant association between RKF (Residual kidney function) and anemia, inflammation, interdialytic weight gain, or serum albumin,2,13,22,23 suggesting that these factors do not explain the differences in symptoms we observed. The explanation for the present study not confirming some previously noted associations is unclear but might reflect the overall good control of nutrition, inflammation, anemia, and mineral metabolism in our cohort. In addition, our study may have lacked sufficient power to detect some of these differences.

Despite recommendations from some guidelines, RKF (Residual kidney function) is not routinely factored into HD (hemodialysis) prescription and measures of HD (hemodialysis) adequacy. This is likely due to concerns regarding the inconvenience of timed urine collections, further compounded by the complexity and lack of consensus regarding the methods for integrating the continuous clearance of RKF with the intermittent clearance of HD (hemodialysis). In our study, we adopted Gotch and Leypoldt’s fixed volume equation to convert intermittent dialyzer clearance into weekly equivalent continuous clearance – StdKt/V.24 In the current study, the mean renal StdKt/V in patients with KRU ≥1 mL/min/1.73 m2 was 0.67, contributing 33.5% of the recommended KDOQI weekly StdKt/V target of 2.0,25 and renal StdKt/V contributed to up to 38% of the total StdKt/V in our patient cohort. Patients with higher RKF levels had higher total StdKt/V despite receiving a lower dialysis dose, highlighting the significant role of RKF (Residual kidney function) in overall solute clearance.

Relevant limitations of this study relate to its observational and cross-sectional nature, the limited size of the study population, and the fact that it is limited to a single center. Hence, our study was not designed to be able to confirm the effect of RKF (Residual kidney function) on hard outcomes such as mortality, that have previously been identified by others.2,13 Due to the observational nature of the study, it is not possible to demonstrate the causality of RKF (Residual kidney function) in affecting any of the observed different outcomes between groups. Another limitation in the study is the relatively high proportion of anuric patients in the cohort. Despite the limitations, the present study confirms the previously observed relationship between RKF and uraemic solute clearance as measured by serum β2M and urea kinetics and extends this with novel findings in relation to symptom burden and potassium homeostasis. Larger multicenter studies are recommended to study these relationships further.

Conclusion

This study provides a signal for the beneficial effects of RKF (Residual kidney function) in HD (hemodialysis) patients. We observed a relationship between RKF (Residual kidney function), as defined by KRU, with lower symptom burden, improved middle molecule clearance, greater total urea clearance, and lower serum potassium. These results raise the possibility that routine monitoring of RKF (Residual kidney function) may be warranted and strategies to preserve RKF in HD patients may improve patient outcomes. Further studies are needed to validate and understand the benefits conferred by RKF in the HD (hemodialysis) patient population, and the role of RKF (Residual kidney function) in the care of ESKD patients managed with HD (hemodialysis).

Acknowledgments

Thanks to the nursing staff in the HD (hemodialysis) units who assisted with the collection of data.

From: ' Relationship between residual kidney function and symptom burden in hemodialysis patients' by Jessica H. Kong

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