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Vitamin C supplementation in kidney failure: Effect on uraemic symptoms

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Nephrol Dial Transplant (2011) 26: 614–620
doi: 10.1093/ndt/gfq412
Advance Access publication 13 July 2010
Vitamin C supplementation in kidney failure: effect on
uraemic symptoms
Richard Francis Singer
The Canberra Hospital Renal Service, Australian National University Canberra, ACT, Australia
Correspondence and offprint requests to: Richard Francis Singer; E-mail: richard.singer@act.gov.au
Abstract
Background. Vitamin C (ascorbate) deficiency and symp-
toms consistent with deficiency (fatigue, myalgia, dyspnoea,
gingivitis, cardiovascular instability and depression) are
common in patients with renal failure. This study aimed to
determine if supplementation with ascorbate in patients with
severe renal failure improved symptoms or cardiovascular
stability, or was associated with adverse effects.
Methods. The study was a 3-month, double-blind, rando-
mized trial of ascorbic acid 250 mg or matching placebo
given thrice weekly. Subjects were clinically stable and either
received conventional dialysis or had an estimated glomeru-
lar filtration rate of <20 mL/min. Symptoms were measured
© The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
For Permissions, please e-mail: journals.permissions@oxfordjournals.org
R.F. Singer
38. Langham RG, Kelly DJ, Gow RM et al. Increased expression of
urotensin II and urotensin II receptor in human diabetic nephropathy.
Am J Kidney Dis 2004; 44: 826–831
39. Balat O, Aksoy F, Kutlar I et al. Increased plasma levels of urotensin-
II in preeclampsia-eclampsia: a new mediator in pathogenesis? Eur J
Obstet Gynecol Reprod Biol 2005; 120: 33–38
40. Balat A, Pakir IH, Gok F et al. Urotensin-II levels in children with
minimal change nephrotic syndrome. Pediatr Nephrol 2005; 20:
42–45
41. Richards AM, Nicholls MG, Lainchbury JG et al. Plasma urotensin II
in heart failure. Lancet 2002; 360: 545–546
42. Heller J, Schepke M, Neef M et al. Increased urotensin II plasma
levels in patients with cirrhosis and portal hypertension. J Hepatol
2002; 37: 767–772
43. Thompson JP, Watt P, Sanghavi S et al. A comparison of cerebro-
spinal fluid and plasma urotensin II concentrations in normotensive
and hypertensive patients undergoing urological surgery during
spinal anesthesia: a pilot study. Anesth Analg 2003; 97: 1501–1503
44. Stangl K, Bartsch C, Richter C et al. Plasma levels and cardiovascu-
lar expression of urotensin-II in human heart failure. Eur Heart J
2001; 22: 348A
45. Cohen GA, Goffinet JA, Donabedian RK et al. Observations on de-
creased serum glutamic oxalacetic transaminase (SGOT) activity in
azotemic patients. Ann Intern Med 1976; 84: 275–280
46. Douglas SA, Behm DJ, Aiyar NV et al. Nonpeptidic urotensin-II
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Received for publication: 28.12.09; Accepted in revised form: 22.6.10
using the Kidney Dialysis Quality of Life-Short Form
(KDQOL-SF ™ ) symptom subscale, and the study was
80% powered to detect a change of 10 in the KDQOL-SF™.
Results. Ninety-nine subjects were randomized, and ascor-
bate deficiency was present in 40% at baseline. Mean symp-
tom scores at follow-up were similar in the two groups
(P-value = 0.19). There was a trend to slightly worse nau-
sea scores in the ascorbate group after controlling for the
level of baseline nausea (P = 0.09), and there was no impact
on cardiovascular stability. Compliance appeared adequate
at 91%, and deficiency was corrected in most (85%) of the
subjects in the active treatment group.
Ascorbate in kidney failure study
Conclusions. This study indicates that ascorbate supple-
mentation does not improve symptoms or cardiovascular
stability in those with severe renal impairment, but is asso-
ciated with a trend towards worse nausea.
Keywords: ascorbic acid ; hypotension; kidney failure; quality of life;
renal dialysis
Introduction
Low vitamin C (ascorbate) levels are rare in the commu-
nity [1] but common in both haemodialysis (HD) [2–4]
and peritoneal dialysis (PD) patients [5,6]. The detrimental
effects of ascorbate deficiency (scurvy) have been recog-
nized for over a hundred years, and the correlation between
blood levels and scorbutic symptoms has been delineated
in more recent human studies [7–9]. This has lead to a def-
inition of ascorbate deficiency as a level <11.4–17 μmol/L
(2–3 mg/L). A level of <23 μmol/L (4 mg/L) is considered
‘insufficient’ because deficiency would be expected after
several days of reduced intake [10].
In dialysis patients, ascorbate deficiency cannot be de-
tected by clinical means as dietary intake correlates poorly
with serum levels [5,6]. Further complicating clinical as-
sessment in the chronic kidney disease population (CKD)
is that scorbutic symptoms such as fatigue, bleeding, ar-
thralgias, myalgias, dyspnoea, peripheral oedema, gingi-
vitis, cardiovascular instability and depression are also
commonly seen in uraemia. It is therefore possible that
some of the symptoms commonly attributed to uraemia
are related to co-existent ascorbate deficiency. Only one
small study has looked at the effect of low-dose supple-
mentation (300 mg ascorbate per week) on symptoms in
dialysis patients [11]. This small, quasi-randomized un-
blinded study found no benefit on quality of life with
supplementation. There is currently no Australian guide-
line for ascorbate supplementation in renal failure pa-
tients, but the potential risks of excessive ascorbate are
warned against in the Australian guidelines [12]. Most
previous studies indicate that ascorbate supplementation
in dialysis patients equivalent to 120–130 mg/day does
not cause adverse effects [6,13,14], although serum oxalates
were not measured in these studies. One study did suggest
an increase in the overall rate of adverse effects with ascor-
bate [11], but the relationship to the medication in that study
was doubtful.
Materials and methods
The primary objective of this study was to determine if supplementation
with 250 mg oral ascorbic acid thrice weekly in patients with severe renal
failure reduced symptoms associated with ascorbate deficiency. The other
objective of the study was to investigate (i) the relationship of ascorbate
deficiency and symptoms in CKD, (ii) the effect of supplementation on
cardiovascular stability in haemodialysis, (iii) the frequency of infections
and (iv) the effect on the rate of loss of native kidney function.
The study design was a prospective, single-centre, double-blind, ran-
domized, placebo-controlled trial. All patients who appeared to meet the
selection criteria on the basis of information recorded in the Canberra
615
Hospital databases were approached for their consent to participate. Those
meeting the selection criteria had baseline data collected and entered
randomization. Enrolment was planned to cease when 150 patients had
been enrolled, or 15 months after recruitment commenced. The study
was listed with the Australia and New Zealand Clinical Trials Registry
(registry number ACTRN12608000016336) and approved by the Austra-
lian Capital Territory Health Human Research Ethics Committee. It was
conducted in accordance with the Declaration of Helsinki. The study was
part funded by the Canberra Hospital Private Practice Fund, with the
remaining funding derived internally from the Canberra Hospital Renal
Unit. All subjects provided written informed consent. The author de-
signed the study, analysed the data and wrote the paper.
Inclusion criteria
Subjects were either receiving thrice weekly maintenance haemodialysis
therapy or receiving maintenance peritoneal dialysis therapy (defined as
having a PD catheter in situ that was being used or planned to be used
within 2 months of enrolment), or had severe renal failure not on dialysis
which was defined as an estimated glomerular filtration rate (eGFR) of
<20 mL/min corrected for body surface area (BSA) as measured by the
four-variable Modification of Diet in Renal Disease (MDRD) equation
[15] with race assumed to be White.
Exclusion criteria
Subjects unable to give informed consent, concurrently enrolled in
another clinical intervention trial, aged less than 18 years, who were
clinically unstable, having a life expectancy <3 months, using ascorbate
supplements within previous 2 weeks, not willing to abstain from non-
study ascorbate supplements for the duration of the study, who lacked
fluency in English or who had previous diagnosis of primary hyperox-
aluria were excluded.
Randomization and intervention
Randomization was by computer-generated random number with subjects
stratified according to diabetic status and by the need for maintenance
dialysis treatment.
Subjects were given a bottle containing 36 capsules with instructions
to take one study capsule three times a week (post-dialysis for HD sub-
jects) for 3 months. Study drugs were compounded and packaged by an
external pharmacy. Active (250 mg ascorbic acid) and placebo (lactose)
capsules were identical in appearance and taste. Both the subjects and
investigators were blinded as to allocation until after the final subject
had completed the study, and all follow-up data had been collected. Oral
dosing was used because intravenous dosing offered no advantage and
was considered impractical for non-haemodialysis subjects.
Outcomes and data collection
The primary outcome of the study was the effect of ascorbate supplemen-
tation on the Kidney Dialysis Quality of Life-Short Form version 1.3
(KDQOL-SF™) symptom subscale [16]. The KDQOL-SF™ is a well-
accepted test for measuring quality of life in dialysis patients, and has
acceptable consistency, with repeated measure correlation of 0.73 for
the symptom subscale [17]. Higher scores indicate better quality of life.
The KDQOL-SF™ symptom and cognitive subscales were administered
either face to face or by telephone by a single research assistant. Baseline
and follow-up data were collected prospectively with confirmation by
examination of the clinical record. Racial affiliation was self-assessed
by subjects. Vascular disease was defined as a history of a revasculariza-
tion procedure or a history of acute myocardial infarction. Adequacy of
blinding was assessed by asking subjects whether they felt they had been
given active or placebo at the completion of the study. Compliance was
assessed by means of a capsule count at the completion of a 3-month fol-
low-up and by analysing changes in plasma ascorbate levels. Compliance
was defined as subjects taking 90% or more of the prescribed capsules.
Supplementation success (which encompasses both compliance and dose
effectiveness) was defined as a rise in ascorbate levels of >11 μmol/L at a
3-month follow-up. A rise of this magnitude is sufficient to eliminate de-
ficiency, regardless of baseline level. Data collection methods and defini-
616 R.F. Singer
Table 1. Secondary outcome definitions and data collection methods

Definition Collection method

Cardiovascular instability A fall in blood pressure during dialysis Pre-printed sheet placed in dialysis notes,
necessitating either a fluid bolus, with confirmation from the clinical record
slowing of ultrafiltration or Trendelenburg
positioning
Bacteraemia Growth of bacteria from blood cultures Pathology Department database
Adverse effects Any event that the patient or investigator Open-ended question at a 3-month follow-up
thought might have been due to study with specific separate questioning for nausea
medication and worsening of diarrhoea
Residual renal function Residual glomerular filtration rate in Renal Unit databases
PD subjects assessed using standard
methods [23]
Three-variable MDRD equation for
non-dialysing subjects (race was
ignored) [15]

tions for the secondary outcomes in the trial are summarized in Table 1,
with native kidney function reported as an eGFR. Ascorbate levels were
measured by high-performance liquid chromatography [18] with the
plasma being centrifuged and deproteinized within 2 h.
Statistical analysis
Analysis was by intention-to-treat (randomized group) with all P-values
two-sided. The null hypothesis was rejected at a significance level of
<0.05. It was pre-specified that analyses were to be repeated for the sub-
group with ascorbate deficiency. A t-test was used for the comparisons of
normally distributed means. Medians were compared using the Wilcoxon
rank-sum test. Cardiac instability was analysed using the method of
Wei–Lin–Weissfeld [19] for correlated Cox regression; however, given
that censoring was insignificant through the study, cardiac instability
was also analysed by the somewhat more familiar method of negative
binomial regression. The method used for calculating P-values for other
data comparisons is indicated in the text by means of a superscript
symbol as follows: ΞWilcoxon signed-rank test, ¶chi-square, §Fisher
exact test, Θordered logistic regression and &binomial probability. Mul-
tiple logistic regression models were compared using a process of back-
ward selection with model comparison by the likelihood ratio test.
Power analysis assumptions
The study was powered at 80% to detect a clinically significant change of
10 in the KDQOL-SF™ symptom subscale with a two-tailed alpha of
0.05. The calculations were based on data suggesting that the distribution
of KDQOL-SF™ symptom subscale scores in haemodialysis patients
would be normally distributed, without a significant ceiling effect, with
a mean of 71 and standard deviation of 16.6 [16,20]. Using a t-test for
analysing the difference in 3-month KDQOL-SF™ scores, a sample size
of 88 was estimated to provide 80% power to detect a difference in
KDQOL-SF™ of 10 with two-sided alpha of 0.05.
Results
Numbers are expressed as medians with interquartile range
(IQR) in brackets or means with their standard errors (SEM)
unless otherwise indicated. Figure 1 shows the flow of par-
ticipants through each stage in the study. Baseline ascorbate
levels were not available in three subjects. This was due to
mishandling of the samples in two subjects and one subject
refusing venisection. A further one subject withdrew from
the study after randomization and collection of an ascorbate
level, but before completing other baseline data. Data for all
subjects were included until their exit from the study. Most
subjects (87%) classified themselves as of ‘European’ or
‘Australian’ race with one subject being Australian Aborigi-
nal. Subjects classifying themselves as ‘Australian’ were all
of predominantly European descent. The subjects in each
group were well matched (Table 2), and ascorbate defi-
ciency was present in 40% at baseline. Ascorbate prescrip-
tion was largely successful in eliminating deficiency at a
3-month follow-up (Table 3).
Mean symptom scores were not statistically significantly
different between the treatment groups at a 3-month follow-
up (P-value = 0.18). Because the symptom scores were not
perfectly normally distributed (Figure 2), the significance
test was repeated using the non-parametric Wilcoxon rank-
sum test to check for any sensitivity of the P-value to the
use of a parametric test. Very similar significance results
were found using this more conservative approach. Limit-
ing the analysis to subjects who were ascorbate deficient at
baseline suggested a non-statistically significant trend to-
wards worse scores in ascorbate-supplemented subjects
who were deficient at baseline (absolute difference in mean
symptom scores = 10.8, P-value = 0.07). However, this
trend was not apparent when baseline symptom scores were
controlled for in a linear regression model limited to ascor-
bate-deficient subjects at baseline (ascorbate therapy beta-
coefficient −4.47, P-value = 0.20). Limiting the analysis of
3-month symptom scores to include only symptoms most
relevant to adult ascorbate deficiency—muscle soreness,
itchy skin, dyspnoea and fatigue (questions 14a, d, f
and i in the questionnaire) [7,10,21]—did not affect the
results. There was no significant relationship between the
presence of baseline ascorbate deficiency and subscale
scores, nor to the severity of any individual component
of the subscales. Analysis of subjects in the active group
as ‘before and after’ pairs did not reveal any significant
effect of ascorbate prescription on either cognitive or symp-
tom scores.
Median 3-month nausea scores were slightly, but not sta-
tistically significantly, worse in the ascorbate group [median
100 (IQR 50–100)] compared with the placebo group [me-
dian 100 (IQR 75–100)] (P-value = 0.056). To check if this
trend was due to an effect of differing baseline scores be-
tween the groups, the nausea scores were reanalysed in an
ordered logistic regression model which controlled for the
Ascorbate in kidney failure study
Fig. 1. Participant flow diagram.
level of baseline nausea. In this model, the trend was weaker
(P-value = 0.09).
More than half of the 65 subjects on haemodialysis dur-
ing the study had at least one episode of cardiovascular in-
stability, but there was no difference between the treatment
groups (P-value = 0.36¶). There were a total of 129 cardio-
vascular instability events during the study (range per sub-
ject 0–13). Analysis using correlated proportional hazards
modelling and negative binomial regression yielded similar
non-statistically significant results, with a hazard ratio of
617
0.87 (P-value = 0.74) in the proportional hazards model.
These results did not change if only ascorbate-deficient sub-
jects at baseline were included, nor when the regression
model controlled for other potential risk factors for cardiac
instability such as diabetes, dialysis vintage or a history of
cardiovascular disease.
Information on native renal function was available for 30
(88%) non-haemodialysis subjects, and the post hoc esti-
mated minimal detectable difference in native renal function
between groups (for beta of 0.2 and alpha of 0.05) was
618 R.F. Singer
Table 2. Baseline characteristics

Ascorbate group (n = 49) Placebo group (n = 50) P-value

Age (SEM) 65.2 (1.81) 63.2 (2.10) 0.47

Male 32 (65%) 36 (73%) 0.38¶
Non-dialysis 12 (24%) 12 (24%)
Peritoneal dialysis 5 (10%) 5 (10%)
Haemodialysis 32 (65%) 33 (67%) 1.0&
Years on dialysis (IQR) 1 (0–3.25) 2 (0.14–3.7) 0.39
Diabetes mellitus 21 (43%) 18 (37%) 0.54¶
History of vascular disease# 19 (39%) 21 (43%) 0.68¶
Lower limb ulceration 1 (2%) 5 (10%) 0.20§
Symptom score (SEM) 78.24 (2.23) 80.23 (1.85) 0.50
Cognitive score (IQR) 93 (73–100) 93 (73–100) 0.60
Plasma ascorbate μmol/L (SEM) 25.5 (4.25) 27.97 (5.54) 0.72
Ascorbate level <11.4 μmol/L 17 (36%) 21 (44%) 0.45¶
Ascorbate level <23 μmol/L 31 (65%) 31 (66%) 0.89¶

#
Confirmed past myocardial infarction or arterial revascularisation.

Table 3. 3-month follow-up data

Ascorbate group (n = 48) Placebo group (n = 48) P-value

Symptom score (SEM) 76.78 (2.52) 80.94 (1.77) 0.18

Cognitive score (IQR) 93.33 (70–100) 90 (76.7–100) 0.65
Nausea score (IQR) 100 (50–100) 100 (75–100) 0.09Θ
Plasma ascorbate μmol/L (SEM) 45.40 (5.78) 20.90 (4.56) 0.001
Plasma ascorbate <11.4 μmol/L 7 (14.6%) 24 (50%) <0.0005§
Plasma ascorbate <23 μmol/L 13 (26.5%) 37 (74%) <0.0005§

Θ
Reported P-value is for the multivariate model controlling for baseline nausea.

4 mL/min/1.73 m2 BSA. In fact, the difference observed was
smaller than this with a mean 3-month eGFR of 11.93 mL/
min/1.73 m2 in the placebo group and 14.5 mL/min/1.73 m2
BSA in the ascorbate group (P-value = 0.20). Controlling for
baseline native renal function in a linear regression model
did not significantly alter this finding. During the study,
there were no episodes of acute coronary syndrome, and
two subjects commenced dialysis, both to the PD modality.
There were too few bacteraemias (two in ascorbate group
and one in placebo group) and dialysis access thromboses
(one in ascorbate group) to analyse differences between
the groups.
Placebo Group Ascorbate Group
100
Univariate predictors for the presence of baseline ascor-
bate deficiency were haemodialysis status [odds ratio 3.88
(P = 0.009)] and years on dialysis [odds ratio 1.13 (P =
0.036)]. Inclusion of both variables in a multivariate logis-
tic regression model indicated that the best model included
only a single independent variable, haemodialysis versus
non-haemodialysis status.
Compliance assessment was suboptimal as only 64 sub-
jects returned their study medication bottles at the comple-
tion of the study. A total of four subjects (two in each
group) had four or more capsules remaining at study
end. Questioning subjects who failed to return their medi-
cation bottle revealed a further two non-compliant sub-
jects, indicating that overall compliance was at best 91%.
Using ascorbate levels to determine the success of treat-

ment encompasses both subject compliance and the effect-

iveness of the prescribed dose. It is also partly dependent
on baseline ascorbate levels, because ascorbate losses on
80

dialysis are proportional to plasma levels, so the likelihood

Symptom Score

of supplementation success will fall as baseline ascorbate

levels rise. Supplementation was successful in raising as-
60

corbate levels by >11 μmol/L in 26 (55%) of the ascorbate

group, compared with only 3 (6%) of the placebo group.
40

Limiting the analysis of supplementation success to those

subjects thought to be compliant on the basis of pill counts
did not significantly affect these percentages.
20

Blinding appeared to be adequate with 70 subjects

stating that they were uncertain which medication they
had been given, 10 guessing correctly and 16 guessing
Fig. 2. KDQOL-SF™ symptom scores at 3 months. incorrectly.
Ascorbate in kidney failure study
Discussion
Ascorbate deficiency was common, and supplementation
was largely (but not entirely) successful in eliminating defi-
ciency in this study; however, despite this, no improvement
in symptoms was seen. The study was adequately powered,
and non-adherence to treatment was relatively low. The fail-
ure to completely eliminate deficiency in the ascorbate
group is a limitation in the study, and would be expected
to somewhat reduce study power. However, given that
symptom scores were numerically worse in those prescribed
ascorbate, it is unlikely that complete elimination of defi-
ciency would have resulted in a positive outcome in this
trial. A higher ascorbate dose may have better eliminated de-
ficiency in the ascorbate group at 3 months, but would also
have increased the risk of adverse effects, particularly the
risk of oxalosis [22]. It is unlikely that inclusion of subjects
that were ascorbate replete at baseline significantly diluted
the effect of treatment, because after controlling for baseline
symptom scores, subgroup analysis limited to subjects de-
ficient at baseline yielded similar results. The study design
deliberately did not limit enrolment to those that were ascor-
bate deficient because it was considered that treating sub-
jects known to be deficient with placebo would have been
unethical. Other possible reasons for the negative result are:
the cut-off defining ascorbate deficiency was incorrect, de-
ficient subjects were truly asymptomatic or the KDQOL-
SF™ performed poorly in detecting symptoms of ascorbate
deficiency.
Despite the compelling experimental data that relate
symptom onset to specific levels of plasma ascorbate in those
with normal renal function, the cut-offs defining defi-
ciency may not apply to the current study. The method of
ascorbate analysis may be different (the exact assay is not
described in the experimental ascorbate deficiency papers)
[7–9]. However, in a population study, where a similar as-
corbate assay was used, the levels considered ‘deficient’
(<11.4 μmol/L) were not seen [1]. It is therefore likely that
such levels are truly consistent with a deficiency state, and
might very well be expected to result in symptoms, as
there is no reason to suspect that subjects with renal failure
would not experience similar symptoms from deficiency.
These symptoms may however become difficult to detect,
among the ‘noise’ of concomitant uraemia, using the
KDQOL-SF™. Support for this contention is the lack of a
relationship between baseline ascorbate deficiency and
symptoms in this study. This would indicate a lack of sensi-
tivity of that instrument for measurement of ascorbate defi-
ciency symptoms. Since the KDQOL-SF™ is validated to
measure symptoms commonly present in renal failure, and
since ascorbate deficiency appears to be common in this
group, it follows that the relative contribution of ascorbate
deficiency to symptoms in those with renal failure is prob-
ably low. For similar reasons, it is unlikely that ascorbate
deficiency plays a significant role in intra-dialysis cardiac
instability.
The findings of this study do not support routine ascor-
bate supplement to improve quality of life in those with
severe renal failure, nor do they suggest a benefit in redu-
cing the frequency of haemodialysis instability. The results
619
do however suggest that supplementation is associated
with few short-term adverse effects and that a fixed low-
dose supplement is not adequate to eliminate deficiency in
all patients. Therefore, if a decision is made to supplement
ascorbate, it would be prudent for the plasma levels to be
checked periodically to ensure that the minimum neces-
sary dose is prescribed to correct deficiency and to con-
sider supplementation as a contributor to any increase in
nausea.
Acknowledgements. I acknowledge Ms Patricia Johnson (The Canberra
Hospital Renal Service) for assistance with subject recruitment and data
collection and Dr Teresa Neeman (Statistical Consulting Unit, Australian
National University) for assistance with statistical analysis.
Conflict of interest statement. None declared.
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Received for publication: 20.4.10; Accepted in revised form: 21.6.10

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doi: 10.1093/ndt/gfq435
Advance Access publication 19 July 2010

Decreased incidence of lupus nephritis in northern Norway is linked to

increased use of antihypertensive and anticoagulant therapy

Gro Østli Eilertsen1, Silje Fismen2, Tor-Arne Hanssen2 and Johannes C. Nossent1,3
1
Department of Rheumatology, Institute of Clinical Medicine, Medical School, University of Tromsø, Norway, 2Department of
Pathology, University Hospital of Northern Norway, Tromsø, Norway and 3Department of Rheumatology, University Hospital of
Northern Norway, Tromsø, Norway
Correspondence and offprint requests to: Gro Østli Eilertsen; E-mail: gro.ostli.eilertsen@unn.no

Abstract (82LN+; n = 28). Following LN diagnosis, more 97LN+

Background. Lupus nephritis (LN) remains a severe
complication in systemic lupus erythematosus (SLE).
Over the last decade, antiphospholipid antibodies have
become a part of SLE classification criteria, and aware-
ness of cardiovascular morbidity and its risk factors in
SLE has increased. This study investigated the potential
effect of these alterations on the presentation and sever-
ity of LN.
Methods. This is an observational study of two subsequent
SLE inception cohorts based on 1982 American College of
Rheumatology (acr) classification criteria (82acr; n = 87,
enrolled 1978–95) and the updated version in 1997
(97acr: n = 62, enrolled 1996–2006). Annual incidence
rates (AIR), point prevalence, clinical and histological fea-
tures, and outcome of LN (defined as proteinuria with
urinary casts and/or haematuria) were compared between
both cohorts.
Results. Between 1978 and 2006, the AIR for LN de-
creased from 0.7 to 0.45/100 000, while LN prevalence
rose from 7 to 14/100 000. The relative risk reduction in
the 97acr for early- and late-onset LN (>3 months after
SLE diagnosis) was 39% and 42%, respectively. Patients
developing LN in the 97acr cohort (97LN+; n = 11) had
similar demographics, more often low avidity anti-dsDNA
antibodies (Ab) and/or anti-cardiolipin Ab at SLE diagno-
sis, lower proteinuria and diastolic blood pressure, and
similar histological findings to those in the 83acr cohort
patients received pulse corticosteroids (55% vs. 7%), antic-
oagulants (46% vs. 4%) and antihypertensive drugs (46%
vs. 11%). Three 82LN + patients (11%) developed end-
stage renal disease versus none in 97LN+ during a 10-
year follow-up.
Conclusions. Early detection of low avidity anti-dsDNA
and antiphospholipid antibodies, probably in combin-
ation with early use of protective cardiovascular mea-
sures from SLE diagnosis onwards may contribute to
reduced incidence and improved renal survival in LN.
Keywords: antibodies; epidemiology; hypertension; lupus nephritis;
survival
Introduction
Renal disease is one of the most serious complications in
patients with systemic lupus erythematosus (SLE). The
pathogenesis of lupus nephritis (LN) is not fully understood
but involves a complex interplay between renal infiltrating
leucocytes, cytokines, autoantibodies and complement
factors [1], which results in immune complex-mediated
glomerulonephritis. In addition, thrombotic and inflamma-
tory vascular lesions may occur that directly affect intrare-

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