Effect of Hemodiafiltration on the Progression of Neuropathy with Kidney Failure

A Randomized Controlled Trial

Abstract

Visual Abstract

Background and objectives 

Neuropathy is a common complication of kidney disease that lacks proven disease-modifying treatments. Hemodiafiltration improves clearance of uremic toxins and is associated with better nerve function than hemodialysis. We aimed to determine whether hemodiafiltration reduces the progression of neuropathy in people receiving hemodialysis.

Design, setting, participants, & measurements 

The Filtration in the Neuropathy of End-Stage Kidney Disease Symptom Evolution (FINESSE) study was an open-label, blinded end point assessment, controlled trial that randomized maintenance hemodialysis recipients to hemodiafiltration or high-flux hemodialysis for 48 months or until death or cessation of dialysis at four study centers. The primary outcome was the mean change in the yearly modified total neuropathy score from baseline, with time points weighted equally.

Results 

A total of 124 participants were randomized and followed for a mean of 41 months. At baseline, neuropathy was present in 91 (73%) participants (modified total neuropathy score greater than or equal to two), and 38 (31%) had moderate to severe neuropathy (modified total neuropathy score 9–28). Convection volume in the hemodiafiltration arm was a median of 24.7 (interquartile range, 22.4–26.5) L. The mean modified total neuropathy score (SEM) worsened by 1.7 (0.4)/28 and 1.2 (0.4)/28 in the hemodiafiltration and hemodialysis groups, respectively, with a mean difference of 0.5 (95% confidence interval, −0.7 to 1.7; P=0.37). There was no difference in survival (hazard ratio, 1.24; 95% confidence interval, 0.61 to 2.51; log rank P=0.55) or any of the prespecified adverse events. There was no difference between groups in the number of participants who suffered an adverse event adjusted by follow-up time (relative risk, 1.05; 95% confidence interval, 0.83 to 1.32; P=0.68).

Conclusions 

Neuropathy is still a common complication of kidney disease without disease-altering therapy. Hemodiafiltration did not affect neuropathy progression compared with hemodialysis.

Clinical Trial registry name and registration number: 

Filtration in the Neuropathy of End-Stage Kidney Disease Symptom Evolution (FINESSE), ACTRN12609000615280

Introduction

Neuropathy is a common but under-recognized complication of CKD without disease-modifying treatment (¹). The sensorimotor polyneuropathy results in discomfort, loss of sensation, weakness, and muscle wasting and leads to disability and poor quality of life (¹,²).

Our understanding of uremic neuropathy has changed over time. In the 1960s, it was described as a severe disease affecting people with uremia (³), but it is now seen as a common complication of CKD with varying severity (⁴). Over this time, there were concurrent advances in dialysis care and nerve conduction studies, allowing detection of milder disease and perhaps reducing the frequency of severe disease (⁵,⁶). There is no definitive test to determine if neuropathy is caused by uremia, diabetes mellitus, or other causes of neuropathy, but neuropathy is found in people with stage 3 CKD without other potential causes of neuropathy (⁷,⁸). Largely on the basis of cross-sectional studies, the prevalence of neuropathy increases with worsening kidney disease, affecting up to 80%–100% of dialysis recipients (⁶,^8910–11), which suggests that cumulative exposure to uremic toxins may underlie the pathogenesis of uremic neuropathy.

Convective therapies (hemodiafiltration or hemofiltration) provide greater clearance of middle molecules than standard hemodialysis and are an attractive potential treatment for uremic neuropathy. Two observational studies found an association between commencing hemodiafiltration and an improvement in nerve conduction study parameters compared with low- or high-flux hemodialysis (¹²,¹³). In addition, a retrospective observational study of incident dialysis recipients between 1983 and 1995 found a reduced need for carpal tunnel surgery in those receiving convective over hemodialysis therapies (¹⁴), putatively related to a reduction in β2-microglobulin and subsequent dialysis-related amyloidosis.

No previous randomized trials have evaluated the effect of hemodiafiltration on neuropathy (¹⁵). We sought to determine whether hemodiafiltration compared with high-flux standard hemodialysis reduced the progression of neuropathy in people receiving maintenance hemodialysis therapy using a multicenter randomized controlled trial.

Materials and Methods

Study Design

The study design was described previously (¹⁶). In brief, the Filtration in the Neuropathy of End-Stage Kidney Disease Symptom Evolution (FINESSE) study was a multicenter, parallel-arm, open-label, blinded end point assessment, prospective randomized controlled trial comparing the effect of hemodiafiltration with high-flux hemodialysis on neuropathy in hemodialysis recipients over 48 months.

Setting

The study was conducted at four dialysis units in Sydney, New South Wales, Australia. Sites were selected for their ability to offer both interventions.

Participants

Adult patients requiring maintenance hemodialysis (incident or prevalent), suitable for either intervention, were eligible. Exclusion criteria were (1) life expectancy <6 months; (2) definite plans to undergo kidney transplantation, transfer to a nonstudy site, or transfer to home dialysis within 12 months; (3) already receiving hemodiafiltration, or (4) unable or unwilling to undergo neurophysiology tests.

Randomization and Masking

Participants were block randomized (block size: four) 1:1 to interventions, stratified by baseline neuropathy score, by an independent statistician. Blinding of participants and physicians was not possible; however, end point assessors, including neuropathy assessors, were blinded.

Intervention

Most hemodiafiltration sessions were postdilutional; however, for 1 year, one site used predilutional hemodiafiltration. No minimum convection volume was specified, although sites were encouraged to use volumes >17.4 L after 2011, when another study reported that higher convection volumes were associated with better survival.

At participating sites, access to hemodiafiltration was limited and restricted to participants randomized to hemodiafiltration in the FINESSE study. All participants received folic acid and B-group vitamins as well as standard dialysis care.

Outcome Measures

The primary outcome was the mean change in the yearly modified total neuropathy score (mTNS) (¹⁷) (Supplemental Table 1) from baseline in accordance with the American Academy of Neurology recommendation (¹⁸). A higher mTNS score indicates worse neuropathy. Neuropathy assessments were performed by three blinded qualified professionals at baseline and 12, 24, 36, and 48 months or prior to exiting the study and duplicated for five participants to assess inter-rater reliability (¹⁷).

Secondary outcomes included survival and access outcomes: thrombosis or requirement for revision of an arteriovenous fistula; time to access failure; and access-attributable systemic infection defined as bacteremia without an identified nonaccess source.

Exploratory outcomes included a rank composite incorporating survival with change in mTNS from baseline; a cardiovascular composite of cardiovascular death or any of the following requiring or occurring during a hospital admission: acute myocardial infarction, stroke, percutaneous coronary or cerebrovascular revascularization, or surgical coronary or cerebral revascularization; surgery for carpal tunnel syndrome; and any adverse events. All outcomes were defined in the prespecified statistical analysis plan (Supplemental Material) prior to unblinding. Events were adjudicated by two blinded assessors (T.B., M.J.J., and A.K.), with discrepancies resolved by discussion or a third assessor.

Laboratory measures (potassium, phosphate, hemoglobin, and β2-microglobulin) were performed locally. Estimates of small solute clearance were used according to usual site practice. Standardized single-pool Kt/V was recorded. The doses of antihypertensives and phosphate binders were assessed at study visits. Convection volume (liters per treatment) was calculated by adding the intradialytic weight loss to the substitution volume. Adherence to allocated intervention (receipt of hemodiafiltration versus hemodialysis) was assessed at study visits. Withdrawal from dialysis or missed dialysis sessions were not captured in adherence. Study visits were conducted at 6-month intervals, with continuous reporting of serious adverse events and access failure events.

Subgroup analyses of the primary outcome were prespecified (sex, dialysis access, dialysis vintage, baseline diabetes status, and baseline mTNS) and chosen to represent the determinants of convective volume and neuropathy severity.

Ethics and Oversight

The study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and it was approved by local health ethics committees at all sites and overseen by an independent data safety monitoring board. All participants gave written informed consent to participate in the study. The FINESSE study was registered with the Australian New Zealand Clinical Trials Registry.

Statistical Analyses

The study had >90% power to detect an mTNS difference of 5.2 between treatment arms. This power calculation assumed a mean mTNS of 9.2 (SD: 7.8) and was inflated assuming a 20% combined dropout and loss to follow-up. Further details of the power calculation were reported previously (¹⁶).

All analyses were performed following intention-to-treat principles. The primary outcome and other continuous end points with repeated measurements over time were modeled using all available time points weighted equally in a linear mixed model including random intercept, randomization, time, and randomization × time categories. All continuous end points, without repeated measurements, were analyzed using linear regression adjusted for the baseline value. Binary repeated measurements were analyzed using a binomial model, and count end points were analyzed using Poisson regression or a negative binomial model if overdispersion was found. Missing data were assumed to be missing at random and were not imputed. Participants who were transplanted, transferred to a nonstudy center, or transferred to peritoneal dialysis were censored at the time of transplantation or transfer. All t tests were two sided, and P values of 0.05 were considered statistically significant. All analyses were conducted using SAS Enterprise Guide 7.1 (SAS Institute Inc.).

The rank composite outcome was determined by ordering participants by their final outcome, first by survival time and then by change in mTNS from baseline. This assumed that the worst outcome is the shortest survival and that the best outcome is survival to 48 months with the largest improvement in mTNS. The log-rank test was used to determine if ranks differed between treatment groups. This analysis was right censored; participants who were transplanted, were transferred, or withdrew consent were assumed to survive until 48 months with their last mTNS carried forward. Participants who were transplanted, were transferred, or withdrew consent prior to having a subsequent mTNS assessment and participants who remained in the study to 48 months without a subsequent mTNS measurement were excluded from this analysis. This methodology was described by the Frequent Hemodialysis Network Group (¹⁹,²⁰) and is an accepted analysis method for studies testing a functional outcome in participants at high risk of mortality or to allow a composite end point to reflect the graded importance of its components (²¹,²²).

Adverse events were assessed as binary or count end points according to the above principles. The risk of a first adverse event was expressed as an odds ratio (OR) or a relative risk if the end point prevalence was high. All adverse events (including multiple events per participant) by treatment group were expressed as a rate ratio. A post hoc analysis of the risk of any adverse event, adjusted by follow-up time, was performed.

Results

Participants

Between July 30, 2009 and April 2, 2014, 124 participants were randomized from four sites: 63 were assigned to hemodiafiltration and 61 were assigned to high-flux hemodialysis. Baseline characteristics were similar between the two treatment groups, excepting White ethnicity, diabetes mellitus, and peripheral vascular disease, which were more common in the hemodiafiltration group (Table 1). At baseline, the mean (SD) mTNS was 6.0 (5.4); 33 (27%) had no neuropathy (mTNS zero or one), 53 (43%) had minor neuropathy (mTNS two to eight), and 38 (31%) had moderate to severe neuropathy (mTNS 9–28).

Table 1. - Baseline characteristics of participants in the Filtration in the Neuropathy of End-Stage Kidney Disease Symptom Evolution study

Characteristics	High-Flux Hemodialysis, n=61	Hemodiafiltration, n=63
Age, yr, mean (SD)	65 (16)	66 (13)
Men, n (%)	33 (54)	36 (57)
Ethnicity, n (%)
White participants	36 (59)	50 (79)
Aboriginal or Torres Strait Islander participants	3 (5)	0 (0)
Maori or Pacific Islander participants	8 (13)	2 (3)
Asian participants	5 (8)	4 (6)
Indian participants	3 (5)	3 (5)
Other participants	6 (10)	4 (6)
Comorbidities, n (%)
Diabetes mellitus	18 (30)	26 (41)
Ischemic heart disease	16 (26)	21/62 (34)
Congestive heart failure	7 (11)	6/62 (10)
Cerebrovascular disease	7 (11)	9 (14)
Peripheral vascular disease	3 (5)	13 (21)
BP, mean (SD)
Systolic	139 (24)	138 (19)
Diastolic	69 (15)	67 (12)
Dialysis characteristics
Dialysis vintage, median (IQR), yr	3.1 (1.2–6.0)	3.2 (1.9–5.2)
Dialysis h/wk, mean (SD)	15.0 (1.1)	14.8 (1.1)
Access, n (%)
Native arteriovenous fistula	45 (74)	51 (81)
Arteriovenous graft	7 (12)	5 (8)
Tunneled dialysis catheter	9 (15)	7 (11)
Blood flow rate, mean (SD), ml/min	300 (18)	304 (19)
Dialysate flow rate, mean (SD), ml/min	500 (0)	500 (0)
Small solute clearance, mean (SD)
Urea reduction ratio	79 (8), n=49	79 (9), n=54
Kt/V single pool	1.51 (0.22), n=12	1.63 (0.20), n=8
Interdialytic weight gain, mean (SD), kg	2.6 (1.5)	2.0 (1.3)
Neuropathy
mTNS, mean (SD)	5.9 (5.1)	6.1 (5.6)
No or minor neuropathy (mTNS 0–8), n (%)	40 (66)	46 (73)
Moderate or severe neuropathy (mTNS 9–28), n (%)	21 (34)	17 (27)
Self-reported peripheral neuropathy, n (%)	8 (13)	7 (12)
Class of medication that may affect nerve function, n (%)	8 (13)	9 (14)

Median (IQR) is presented for skewed data. The denominator is provided when not for the full group. IQR, interquartile range; mTNS, modified total neuropathy score.

Treatment was discontinued before 48 months in 63 participants (51%) due to death (31 participants; 25%), transplantation (18 participants; 15%), transfer to a nonstudy site (ten participants; 8%), and withdrawal from the study (four participants; 3%) (Figure 1), giving mean and median follow-up values of 41 and 49 months, respectively.

Figure 1.: Participant flow in the Filtration in the Neuropathy of End-Stage Kidney Disease Symptom Evolution (FINESSE) study.

Analyzable results for the primary outcome were available for all participants; however, 24 participants (19%) had baseline results only as they were transplanted (seven), were transferred (four), withdrew consent (three), or died (ten) before subsequent assessment could be performed.

Delivered Treatment, Biochemical Clearance, and Intermediate Markers

Adherence to allocated treatment (receipt of hemodialysis versus hemodiafiltration) was 100% in the hemodialysis group, 83% in the hemodiafiltration group, and 91% overall (Supplemental Figure 1).

Treatment characteristics and the effect on biochemical clearance and intermediate markers are shown in Table 2. The median (interquartile range [IQR]) convection volume was 24.7 (22.4–26.5) L (Supplemental Table 2). Over the study period, there was no difference in treatment time, blood flow rate, interdialytic weight gain, BP, or antihypertensive medication requirement between groups.

Table 2. - Delivered treatment and intermediate outcomes

Characteristic	High-Flux Hemodialysis	Hemodiafiltration	Mean Difference (95% Confidence Interval)	P Value
Treatment time, h/wk	14.8 (0.2)	14.8 (0.2)	0.1 (−0.5 to 0.6)	0.79
Blood flow rate, ml/min	302 (1)	301 (1)	−0.4 (−4.1 to 3.4)	0.85
Convection volume, L/treatment a	NA	24.7 (22.4–26.5)	NA	NA
Interdialytic weight gain, kg	2.1 (0.1)	2.3 (0.1)	0.2 (−0.1 to 0.4)	0.24
Systolic BP, mm Hg	138 (2)	139 (2)	0.9 (−4.5 to 6.4)	0.74
Diastolic BP, mm Hg	68 (1)	66 (1)	−1.8 (−5.0 to 1.4)	0.27
Clearance
Single-pool Kt/V b	1.60 (0.04)	1.56 (0.05)	−0.04 (−0.2 to 0.1)	0.56
Urea reduction ratio b	80 (1)	80 (1)	0.8 (−0.9 to 2.5)	0.37
Predialysis β2-microglobulin, mg/L	30.3 (0.9)	28.9 (0.9)	−1.4 (−4.0 to 1.2)	0.28
β2-microglobulin clearance (%)	57.0 (1.3)	66.3 (1.3)	9.4 (5.7 to 13.1)	<0.001
Other laboratory results
Potassium, mEq/L	5.1 (0.1)	5.2 (0.1)	0.1 (−0.1 to 0.2)	0.30
Phosphate, mg/dl	4.8 (0.1)	4.71 (0.2)	−0.1 (−0.5 to 0.3)	0.62
Hemoglobin, g/dl	11.2 (0.1)	11.2 (0.1)	−0.1 (−0.3 to 0.2)	0.68
Medication requirement
Phosphate binder c	4.0 (0.3)	3.6 (0.3)	−0.4 (−1.3 to 0.5)	0.39
Antihypertensive d	0.3 (0.1)	0.3 (0.1)	−0.03 (−0.2 to 0.1)	0.73

Mean difference over time was adjusted by the baseline value. Values are mean (SEM) unless otherwise indicated. NA, not applicable.

^aMedian (interquartile range).

^bSites reported Kt/V or urea reduction ratio according to usual site practice.

^cNumber of tablets per day.

^dNumber of full-dose medications.

There was no difference in predialysis potassium, phosphate, phosphate binder requirement, or small molecule clearance between groups. β2-microglobulin reduction (percentage) per session was greater in the hemodiafiltration arm (mean difference [MD], 9%; 95% confidence interval [95% CI], 6 to 13; 66% for hemodiafiltration versus 57% for hemodialysis; P<0.001). However, predialysis β2-microglobulin was similar between groups (MD, −1.4; 95% CI, −4.0 to 1.2 mg/L; 28.9 mg/L for hemodiafiltration versus 30.3 mg/L for hemodialysis; P=0.28).

Neuropathy Scores and Outcomes

Inter-rater reliability for the mTNS was high (Spearman coefficient: 0.997) (Supplemental Figure 2), similar to the original description of the total neuropathy score (TNS; Spearman coefficient: 0.966) (¹⁷).

Over a mean of 41 months, mTNS (SEM) increased by 1.7 (0.4) and 1.2 (0.4) in the hemodiafiltration and hemodialysis groups, respectively (Figure 2).

Figure 2.: Effect of hemodiafiltration on the primary outcome (change in mean modified total neuropathy score [mTNS] from baseline) in the FINESSE study. A total of 124 participants were included in FINESSE. The primary outcome, the mean change in the mTNS from baseline, is depicted for each group. Error bars depict the SD. The mTNS is scored out of 28 points, and a lower mTNS is a better outcome. The primary outcome was modeled in a linear mixed model using all available yearly time points weighted equally. No imputation was used. The number of participants is displayed as n/N, where n is the number of participants contributing data and N is the total number of participants enrolled in the study at each time point.

Primary Outcome.

There was no difference in the change in mTNS between groups, with an MD of 0.5 (95% CI, −0.7 to 1.7; P=0.37) (Figure 2, Supplemental Table 3). There was also no difference in the change in the mTNS in any of the prespecified subgroup analyses: sex, access type, diabetes status, baseline mTNS, or dialysis vintage (Figure 3) (P value for interaction: all P≥0.20).

Figure 3.: Effect of hemodiafiltration on the primary outcome (change in mean mTNS from baseline) in subgroups. A total of 124 participants were included in the analysis. Subgroups were prespecified. The mean differences between treatment groups are depicted. The mTNS is scored out of 28 points, and a lower mTNS is a better outcome. The primary outcome was modeled in a linear mixed model using all available yearly time points weighted equally. No imputation was used. CI, confidence interval.

Secondary Outcomes.

There were 31 deaths (16 in the hemodiafiltration group and 15 in the hemodialysis group), with no difference in survival (hazard ratio [HR], 1.24; 95% CI, 0.6 to 2.51; log rank P=0.55) (Supplemental Figure 3). There was also no difference in access events (OR, 0.82; 95% CI, 0.38 to 1.78; P=0.86) (Table 3) or time to access failure (HR, 0.92; 95% CI, 0.46 to 1.82; P=0.80).

Table 3. - Secondary and exploratory outcomes

Event	First Events				All Events
	High-Flux Hemodialysis, n=61	Hemodiafiltration, n=63	Risk Estimate (95% Confidence Interval) a	P Value	High-Flux Hemodialysis, n=61	Hemodiafiltration, n=63	Rate Ratio (95% Confidence Interval)	P Value
Secondary outcomes
Death	15	16	1.04 (0.46 to 2.35)	0.92	NA	NA	NA	NA
Cardiovascular	9	5	0.50 (0.16 to 1.58)	0.23	NA	NA	NA	NA
Noncardiovascular	6	11	1.94 (0.67 to 5.62)	0.22	NA	NA	NA	NA
Access failure	19	17	0.82 (0.38 to 1.78)	0.61	37	35	0.92 (0.48 to 1.74)	0.79
Infection related to access b	8	6	0.70 (0.23 to 2.14)	0.53	9	9	0.97 (0.46 to 2.03)	0.93
Exploratory outcomes
Any adverse event	60	49	0.79 (0.69 to 0.91)	0.007	244	222	0.88 (0.62 to 1.24)	0.47
Adjusted by follow-up time	60	49	1.05 (0.83 to 1.32)	0.68	—
Cardiovascular composite	10	9	0.85 (0.32 to 2.26)	0.74	10	16	1.55 (0.75 to 3.19)	0.23
Other (nonaccess) infection	28	29	1.01 (0.50 to 2.04)	0.99	54	58	1.04 (0.64 to 1.70)	0.88
Carpal tunnel syndrome surgery	2	1	0.48 (0.04 to 5.39)	0.55	2	1	0.48 (0.17 to 1.34)	0.16

NA, not applicable.

^aRisk estimate is relative risk for any adverse event and any adverse event adjusted by follow-up time and odds ratio for all other by participant (first event) analyses.

^bIncludes septicemia without defined nonaccess source.

Exploratory Outcomes.

The rank composite of survival and change in mTNS did not differ between the two groups (HR for worse outcome, 1.09; 95% CI, 0.74 to 1.58; log rank P=0.65) (Figure 4).

Figure 4.: Rank composite of survival and change in mTNS from baseline in the FINESSE study. Kaplan–Meier curves represent survival, and in survivors, the change in mTNS from baseline. A total of 110 participants were included in this analysis, as 14 participants were transplanted, transferred, or withdrew consent prior to repeat mTNS and were excluded from this analysis. Each participant was ranked according to the final outcome at the end of the trial, assuming that the worst outcome was the shortest survival (regardless of change in mTNS) and that the best outcome was survival to 48 months and the largest improvement in mTNS. Ranks were compared using the log-rank test.

Fewer participants suffered an adverse event in the hemodiafiltration group compared with the hemodialysis group (relative risk, 0.79; 95% CI, 0.69 to 0.91; P=0.0007); however, there was no difference in the number of people who suffered an adverse event between groups when adjusted by follow-up time (relative risk, 1.05; 95% CI, 0.83 to 1.32; P=0.68) (Table 3). There was also no difference in the total number of adverse events between groups (rate ratio, 0.88; 95% CI, 0.62 to 1.24; P=0.47) or the risk of any of the prespecified adverse events. The cardiovascular composite occurred 26 times in 19 participants: nine participants in the hemodiafiltration group and ten participants in the hemodialysis group (OR, 0.85; 95% CI, 0.32 to 2.26; P=0.74).

Discussion

The FINESSE randomized trial found no difference between the progression of neuropathy in participants allocated to hemodiafiltration compared with those allocated to hemodialysis over 48 months, despite greater middle molecule clearance in the hemodiafiltration arm. FINESSE is the first randomized trial to investigate whether hemodiafiltration improves neuropathy over hemodialysis and also the largest and longest trial in neuropathy in people with kidney disease. The lack of effect was consistent across subgroups (sex, access type, diabetes status, dialysis vintage, and neuropathy severity). We also found no difference in survival or the rank composite of survival and neuropathy progression. Similar to previous studies, hemodiafiltration was safe and did not increase adverse events over hemodialysis.

Hemodiafiltration did not alter the progression of neuropathy, measured using a gold standard assessment of neuropathy, in a cohort of hemodialysis recipients with predominantly minor neuropathy without irreversible damage, and therefore, at the optimal time point for intervention. Participants were followed for 4 years, a sufficiently long period to detect any meaningful effect of hemodiafiltration on neuropathy progression. Hemodiafiltration was delivered according to best practice with adequate biochemical clearances and with an average convection volume of 24.7 L.

Uptake of hemodiafiltation has increased despite the lack of clear evidence of morbidity or mortality benefit and is now used for 10% of hemodialysis recipients globally (²³). Several large observational studies have found an association between hemodiafiltration usage and better survival compared with standard hemodialysis (low or high flux; Dialysis Outcomes and Practice Patterns Study, n=2165 [²⁴]; RISCAVID, n=757 [²⁵]; and the Renal Epidemiology and Information Network registry, n=28,407 [²⁶]). However, these observational studies are limited by selection bias as physicians choose who receives convective therapies, and patients who are unable to achieve adequate convection volumes are more likely to transfer to dialysis. Systematic reviews of randomized trials (¹⁵,²⁷) on the effect of hemodiafiltration on clinical outcomes found no difference in survival and heterogenous findings for cardiovascular events and small molecule clearance, although symptomatic hypotension and middle molecule clearance (β2-microglobulin) were better with hemodiafiltration. Similarly, we found no difference to small molecule clearance but improved serum β2-microglobulin clearance with hemodiafiltration compared with hemodialysis.

Explanations for the differential findings between hemodiafiltration studies include achieved convection volume and selection bias. In hemodiafiltration, solute clearance and efficacy are determined by convection volume. Although there was no overall association between survival and hemodialysis modality in the CONTRAST (²⁸) or Turkish OL-HDF (²⁹) trials, post hoc analyses found an association between higher achieved convection volumes and survival in those allocated to hemodiafiltration. However, one of the main determinants of convection volume is blood flow rate (²⁹,³⁰), which is determined by access type, sex, age, and comorbidities such as diabetes (³¹), in addition to site practice. Many of these factors are also predictors of survival or markers of better health, and risk of residual confounding remains after statistical adjustment for these factors in post hoc analyses. Hemodiafiltration was associated with better survival in the ESHOL study (³²), which targeted a convection volume of >18 L and achieved a median (IQR) of 23.7 (IQR, 23.3–24.1) L. However, participants who did not receive the target convection volume for 2 consecutive months were withdrawn, potentially selecting healthier participants in the hemodiafiltration group, as suggested by the difference in blood and dialysate flow rates between treatment groups at the end of the study. Our achieved convection volume of 24.7 (IQR, 22.4–26.5) L was similar to that achieved in the ESHOL study and higher than the achieved convection volume in the CONTRAST (mean [SD]: 20.7 [6.0]) and Turkish (mean [SD]: 17.2 [1.3]) studies, suggesting that our neutral result is not type 2 error from insufficient convection volumes. The upcoming trials (H4RT [ISRCTN10997319] [³³] and the CONVINCE [NL6942] [³⁴]) in high-efficiency hemodiafiltration will be imperative to resolving the question of whether hemodiafiltration improves survival and cardiovascular events in people receiving hemodialysis.

There are still no disease-modifying treatments for uremic neuropathy. Only two prior randomized trials, to our knowledge, have investigated potential treatments for uremic neuropathy. An Australian study of 47 participants with CKD found that dietary potassium restriction improved TNS and gait speed over 24 months (³⁵). Lastly, a Japanese study of 36 dialysis recipients who were not administered routine vitamin supplementation found that vitamin B6 improved symptoms of neuropathy over 1 month (³⁶).

No single toxin has been identified as the mediator of uremic neuropathy (¹), leading to theories that it is caused by multiple toxins or potassium. In small studies, serum potassium levels correlate with nerve function in dialysis recipients (³⁷), and as aforementioned, a small randomized trial found that dietary potassium restriction improved nerve excitability in people with predialysis CKD. Further studies could assess the role of potassium-lowering therapy in neuropathy, although the scope for manipulation may be limited in people receiving dialysis, where potassium is already aggressively treated with dietary modification and dialysis. Other consequences of aggressively lowering potassium should also be considered, such as the risk of sudden cardiac death observed with low-potassium baths (<2 mEq/L) in large studies (³⁸). Treatments for uremic neuropathy may also alter the trajectory of diabetic neuropathy in people with diabetic kidney disease, who experience markedly accelerated neuropathy compared with those with either disease alone (⁷,³⁹).

Our study also highlights the under-recognition of neuropathy even in people receiving hemodialysis therapy. In our cohort, only 15 (12%) self-reported a diagnosis of neuropathy at baseline, despite a high prevalence of neuropathy; 91 (73%) met the diagnostic threshold for neuropathy, and 38 (31%) had moderate to severe neuropathy.

Few studies have described the natural history of uremic neuropathy. Although cross-sectional studies (^678910–11) suggest that neuropathy progressively worsens with each stage of kidney disease, the rate of progression observed in our study is perhaps slower than that seen in the only other comparable study using a similar neuropathy score in kidney disease, to our knowledge, in stages 3 and 4 CKD (TNS change of 2.8/32 over 2 years) (³⁵). However, as our study is longer, it is possible that the slower rate of progression is the result of survival bias, and this should be assessed further in future studies.

This is the largest and longest trial of neuropathy in kidney disease, utilizing a validated multidimensional assessment tool including symptoms, signs, and nerve conduction study findings. Our findings are generalizable to people receiving dialysis in Australia. Our neuropathy scores were similar to the kidney failure subgroup in the TNS validation in CKD study (⁸), accounting for the exclusion of the vibration domain in our study. Our trial population received optimal modern background dialysis care, receiving dialysis with high-flux membranes for 5 hours and routine vitamin supplementation.

At the time that our study began, there were no longitudinal studies of uremic neuropathy to guide a fully longitudinal power calculation for the progression of neuropathy over time. Without prior information about correlation between repeated measurements in a longitudinal model, we could not complete a longitudinal power calculation. We, therefore, conservatively powered calculations on the basis of a comparison of study arms at the final time point (⁸), the difference between two cross-sectional groups. However, a longitudinal study has more power than a single–time point comparison comparing group means because of the increased precision of SEMs with repeated measures. The small 95% CI of the measured (nonsignificant) difference between the groups (95% CI, −0.7 to 1.7) curtails the possibility of there being a clinically significant difference between arms (prospectively defined as greater than or equal to two points in the mTNS score).

Limitations include that neuropathy progression in the control group was small, allowing only a small opportunity for benefit. In addition, this relatively small trial may not have detected differences in uncommon adverse events or survival, treatment allocation was not blinded to participants or treatment providers, and there were slightly more people with diabetes mellitus and peripheral vascular disease in the hemodiafiltration arm. However, prognostic factors did not favor one arm over the other.

Hemodiafiltration does not improve neuropathy compared with high-flux hemodialysis, and this lack of effect was consistent across subgroups. Hemodiafiltration is safe and improved middle molecule clearance. In addition, there was no difference in survival or the final outcome of participants, incorporating survival with neuropathy progression. Neuropathy remains prevalent in people who receive hemodialysis, and further work should investigate the role of other pathophysiologic mechanisms for uremic neuropathy.

Disclosures

T. Bradbury reports receiving research funding from Glaxo-SmithKline. M. Gallagher reports receiving research funding from Bayer Pharmaceuticals, receiving honoraria from AstraZeneca, and other interests/relationships with The George Institute for Global Health. C. Hawley reports consultancy agreements with Glaxo-SmithKline, Janssen, and Otsuka; receiving research funding from Abbott product supply, Amgen, Baxter, Baxter products supply, Bayer product supply, Cilag, Janssen, and Otsuka; receiving a Shire study grant; receiving honoraria from Janssen (paid to university); receiving GlaxoSmithKline consultancy fees (paid to university); serving as a scientific advisor or member of Otsuka; being involved with consumers in relation to clinical trials and interactions with Kidney Health Australia in these activities; serving on the grants panel for the National Health and Medical Research Council of Australia; and serving as a board member for the Polycystic Kidney Disease Australia Foundation. M.J. Jardine reports consultancy agreements with Akebia, Bayer, Boehringer Ingelheim, CSL, and Vifor; receiving research funding from Amgen, Baxter, CSL, Dimerix, Eli Lilley, Gambro, and MSD; receiving honoraria from Amgen, AstraZeneca, Chinook Therapeutics, Janssen, Roche, and Vifor (directs honoraria to clinical research programs); and serving as a scientific advisor or member of Akebia, AstraZeneca, Baxter, Bayer, Boehringer Ingelheim, CSL, Janssen, and Vifor (directs honoraria to clinical research programs). M.J. Jardine is supported by a cofunded National Health and Medical Research Council Career Development Fellowship and National Heart Foundation Future Leader Fellowship. M.C. Kiernan reports serving as Editor-in-Chief of Journal of Neurology, Neurosurgery and Psychiatry (BMJ Publishers, United Kingdom). V. Perkovic reports consultancy agreements with AbbVie, Astellas, AstraZeneca, Bayer, Baxter, Bristol-Myers Squibb, Boehringer Ingelheim, Dimerix, Durect, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Merck, Metavant, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Pfizer, PharmaLink, Relypsa, Retrophin, Roche, Sanofi, Servier, Tricida, UpToDate, and Vitae; receiving research support from the Australian National Health and Medical Research Council (Senior Research Fellowship and Program Grant); and serving on steering committees for AbbVie, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Novartis, and Pfizer. All remaining authors have nothing to disclose.

Funding

The study was funded by Royal Australasian College of Physicians Jacquot Research Establishment Awards in 2011 and 2012 and an unrestricted grant from Baxter Healthcare Corporation. A nerve conduction study machine was supported by the Concord Hospital Renal Research Trust and the Royal Prince Alfred Hospital Renal Unit Trust. R. Arnold was supported by National Health and Medical Research Council early career fellowship 1091006. M.J. Jardine is funded by a Medical Research Future Fund career development fellowship. A. Kang is supported by National Health and Medical Research Council postgraduate scholarship 1150349 via the University of New South Wales and an Australian Government research training program fee offset and has received a George Institute scholarship. M.C. Kiernan was supported by National Health and Medical Research Council practitioner fellowship 1156093. B. Smyth was supported by a University of Sydney university postgraduate award.