Nephrol Dial Transplant (2006) 21: Editorial Comments
as well as clinical information), e.g. IgA glomerulo-
nephritis.
It is hoped that adherence to such a systematic
procedure will improve the results and heighten the
impact of pathology on clinical decision making.
Conflict of interest statement. None declared.
References
1. Regele H, Mougenot B, Brown P et al. Report from Pathology
Consensus Meeting on Renal Biopsy Handling and Processing,
Vienna, February 25, 2000 (http://www.kidney-euract.org/
Rbpathologyconsensus.htm)
2. Thut MP, Uehlinger D, Steiger J, Mihatsch MJ. Renal biopsy:
standard procedure of modern nephrology. Ther Umsch 2002;
59: 110–116
3. Paone DB, Meyer LE. The effect of biopsy on therapy in renal
disease. Arch Intern Med 1981; 141: 1039–1041
4. Fuiano G, Mazza G, Comi N et al. Current indications for
renal biopsy: a questionnaire-based survey. Am J Kidney Dis
2000; 35: 448–457
Nephrol Dial Transplant (2006) 21: 1161–1166
doi:10.1093/ndt/gfl044
Advance Access publication 20 February 2006
Why is homocysteine elevated in renal failure and
what can be expected from homocysteine-lowering?
Coen van Guldener
Department of Internal Medicine, Amphia Hospital, PO Box 9057, 4800 RL Breda, The Netherlands
Keywords: folic acid; homocysteine;
sulphur amino acids
Patients with chronic kidney disease, especially end-
stage renal disease (ESRD), exhibit many abnormalities
in protein and amino acid metabolism. One of these
alterations involves an increased plasma concentration
of the sulphur-containing amino acid homocysteine.
Hyperhomocysteinaemia has attracted a lot of atten-
tion in renal patients, not only because of its close
relationship with renal function, but also because it has
been implicated as an independent cardiovascular risk
Correspondence and offprint requests to: Coen van Guldener,
Department of Internal Medicine, Amphia Hospital, PO Box 9057,
4800 RL Breda, The Netherlands. Email: cvguldener@amphia.nl
ß The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
For Permissions, please email: journals.permissions@oxfordjournals.org
1161
5. Andreucci VE, Fuiano G, Stanziale P, Andreucci M. Role of
renal biopsy in the diagnosis and prognosis of acute renal
failure. Kidney Int Suppl 1998; 66: S91–S95
6. Cameron JS. Indications for renal biospy, history of the
procedure, and relationship of the findings to further
investigation and treatment. In: Solez K, Racusen L, Olsen S,
eds. Diagnostic Renal Pathology. Transpath Inc. (http://www.
transpath.com/m-media/DRP.htm)
7. Corwin HL, Schwartz MM, Lewis EJ. The importance
of sample size in the interpretation of the renal biopsy. Am J
Nephrol 1988; 8: 85–89
8. McCarthy GP, Roberts IS. Diagnosis of acute renal allograft
rejection: evaluation of the Banff 97 Guidelines for Slide
Preparation. Transplantation 2002; 73: 1518–1521
9. Amann K. New parameters in kidney biopsy diagnostic-
morphometry. Kidney Blood Press Res 2000; 23: 181–182
10. Nickeleit V, Zeiler M, Gudat F, Thiel G, Mihatsch MJ.
Detection of the complement degradation product C4d in renal
allografts: diagnostic and therapeutic implications. J Am Soc
Nephrol 2002; 13: 242–251
11. Böhmig GA, Exner M, Habicht A et al. Capillary C4d deposi-
tion in kidney allografts: a specific marker of alloantibody-
Downloaded from http://ndt.oxfordjournals.org/ by guest on September 24, 2015
dependent graft injury. J Am Soc Nephrol 2002; 13: 1091–1099
Received for publication: 1.12.05
Accepted in revised form: 9.12.05
factor in these patients [1–3], although some recent
studies have found no significant or even an inverse
association between plasma homocysteine level and
cardiovascular events and mortality in ESRD patients
[4–6]. These discordant findings may have been caused
by strong confounders which are associated with low
homocysteine levels and increased mortality, such as
protein energy malnutrition and/or inflammation [7].
Homocysteine and renal function
Plasma homocysteine is strongly correlated with
(estimates of) glomerular filtration rate (GFR).
Hyperhomocysteinaemia, defined as a plasma total
homocysteine level of 12 mmol/l, occurs already at a
GFR of about 60 ml/min and when ESRD has been
1162
reached, the prevalence of hyperhomocysteinaemia is
85–100%. The association between plasma homo-
cysteine and GFR seems linear and is present even in
the hyperfiltrating range [8,9]. The precise mechanism
by which GFR is related to plasma homocysteine
concentration is not definitively established. There is a
reasonably good clinical evidence that hyperhomo-
cysteinaemia does not cause renal insufficiency [10–12],
although a recent study has linked higher homocysteine
levels to a greater decline of GFR [13]. The association
between hyperhomocysteinaemia and renal dysfunc-
tion may therefore be causal, i.e. renal failure causes
elevated plasma homocysteine levels, but the relation-
ship may also be due to other confounding factors,
which on the one hand lead to renal dysfunction and
on the other hand cause hyperhomocysteinaemia by
different mechanisms. Two, not mutually exclusive
hypotheses for the first possibility are: (i) homocysteine
disposal in the kidneys themselves is disturbed and
(ii) extrarenal homocysteine metabolism is impaired.
Factors that cause renal dysfunction and hyperhomo-
cysteinaemia by different mechanisms have not been
identified.
Renal homocysteine metabolism
The close relationship between plasma homocysteine
and GFR suggests that homocysteine is cleared from
the body by urinary excretion after glomerular filtra-
tion, just like creatinine. However, the amount of
homocysteine in the urine is minimal (about
6 mmol/day) [14]. From a normal GFR of 180 l/day
and a free homocysteine concentration of 3 mmol/l, it
can be calculated that 99% of the filtered homocysteine
is reabsorbed. The exact location of this uptake
and the metabolic fate of homocysteine in the tubules
are unknown. Homocysteine transsulphuration and
remethylation enzymes are present in human kidney
tissue, indicating that metabolism is possible. Studies in
the rat have shown that homocysteine is taken up and
metabolized by the kidney [15]. Two studies in humans
with normal renal function, however, did not find a
significant arteriovenous difference in homocysteine
concentration across the kidney [16,17] (Figure 1).
In the study of Garibotto et al. [17], a small renal
homocysteine extraction was found in subjects with a
higher renal plasma flow (>500 ml/min), whereas some
homocysteine release was found when renal plasma
flow was <500 ml/min. Apart from being due to
chance, this finding could also suggest that renal
homocysteine metabolism, if any, would depend on
the renal plasma flow. However, as renal plasma flow
does not largely affect GFR in humans (due to filtration
disequilibrium), this is somewhat contrary to the
general finding that plasma homocysteine is related to
GFR. Furthermore, a larger study failed to establish
a relationship between plasma homocysteine and
effective renal plasma flow [9].
An intrarenal homocysteine disposal, thus, has not
yet been proved, but it may exist in balance with an
Nephrol Dial Transplant (2006) 21: Editorial Comments
A V
KIDNEY
tHcy 10.8 mmol/l tHcy 10.7 mmol/l
fHcy 3.2 mmol/l, fHcy 3.2 mmol/l,
i.e. 576 mmol/day i.e. 576 mmol/day
U Hcy 6 mmol/day
Fig. 1. Homocysteine input and output in the normal kidney.
There is no net renal arteriovenous extraction and only minimal
Downloaded from http://ndt.oxfordjournals.org/ by guest on September 24, 2015
urinary excretion of homocysteine (data from [14] and [16]). tHcy:
total homocysteine, fHcy: free (non-protein bound) homocysteine.
equal rate of homocysteine formation. A preferential
defect in homocysteine disposal could hypothetically
occur in chronic kidney disease and subsequently lead
to hyperhomocysteinaemia. For this theory, however,
there is no supportive evidence, e.g. from renal arterio-
venous studies in renal patients. Also, it should be kept
in mind that loss of renal amino acid metabolism in
chronic kidney disease does not always predict the
consequences on plasma concentrations [18].
Extrarenal homocysteine metabolism
In order to investigate the whole body homocysteine
metabolism in chronic kidney disease, one might
study plasma concentrations of several metabolites.
Homocysteine is generated by demethylation of
methionine, which in turn is derived from exo- or
endogenous proteins. S-adenosylmethionine and
S-adenosylhomocysteine are the intermediates in
this transmethylation pathway. In the remethyla-
tion pathway, homocysteine is reconverted to
methionine by receiving a methyl group from
5-methyltetrahydrofolate, the active form of folic
acid, or betaine. Irreversible disposal of homocysteine
occurs through the transsulphuration pathway, in
which homocysteine condenses with serine to form
cystathionine, which is split into cysteine and alpha-
ketobutyrate. There are several metabolic fates of
cysteine, such as incorporation in proteins and con-
version to metabolites such as 3-mercaptopyruvate,
cysteinesulphinate, gamma-glutamylcysteine or cystine.
The sulphur end product of cysteine metabolism is
sulphate, which is excreted by the kidneys.
In general, patients with renal failure have normal
plasma levels of methionine, betaine and B-vitamins,
elevated levels of S-adenosylmethionine, S-aden-
osylhomocysteine, cystathionine, cysteine and sulphate,
Nephrol Dial Transplant (2006) 21: Editorial Comments
Methionine
RM
Vitamin B12
5-methylTHF
Homocysteine
Betaine
Pyridoxine TS
Cystathionine
Pyridoxine TS
Cysteine
Fig. 2. Sulphur amino acid metabolism in end-stage renal disease. Plasma concentrations or flux rates are similar (grey), increased (black)
or decreased (white) as compared with the normal values. RM: remethylation, TM: transmethylation, TS: transsulphuration, AdoMet:
S-adenosylmethionine, AdoHcy: S-adenosylhomocysteine, 5-methyl THF: 5-methyl tetrahydrofolate (i.e. the active form of folic acid).
and low serine levels [19–24] (Figure 2). Plasma homo-
cysteine shows the strongest relationships with plasma
folate, S-adenosylhomocysteine and cysteine. The two
most obvious explanations for these findings would be
a block in homocysteine remethylation and a distur-
bance in cysteine disposal. Support for the first theory is
based on trials showing that successful homocysteine-
lowering regimens in chronic kidney disease always
include folate. Randomized trials have shown that
different forms of folates and different routes of
administration are equally effective in lowering
plasma homocysteine in ESRD patients [25,26], which
has substantially weakened suggestions that a disturbed
folate metabolism may cause hyperhomocysteinaemia
in chronic kidney disease [27]. Based on high cysteine
and low taurine levels, Suliman et al. [28] proposed that
a block in decarboxylation of cysteinesulphinic acid,
the intermediate between cysteine and taurine, con-
tributes to hyperhomocysteinaemia in CRF. Among
subjects with normal to severely impaired renal func-
tion, Nakanishi et al. [24] found that plasma homo-
cysteine was independently associated with plasma
sulphate and they speculated that retention of sulphate
somehow leads to hyperhomocysteinaemia in chronic
kidney disease.
Results from studies that rely on measurement of
plasma levels of metabolites must be interpreted with
caution. Amino acid metabolism takes place intracel-
lularly and varies between organs and tissues. Plasma
contains only a small fraction of total body free
amino acids and the plasma concentration of an
amino acid depends on the supply from the cellular
and/or interstitial compartment and the disposal
from plasma. Elevated or decreased concentrations
are indicative of a disturbed metabolism, but normal
concentrations do not exclude abnormalities, because
1163
AdoMet
TM
AdoHcy
Serine
Sulphate
Downloaded from http://ndt.oxfordjournals.org/ by guest on September 24, 2015
the rates of synthesis and elimination may be altered
in the same direction. In addition, regulation of
amino acid metabolism is influenced by feeding.
Measurements in the post-absorptive state may there-
fore not provide a complete picture of amino acid
metabolism.
Our group has used a stable isotope method to study
the whole body sulphur amino acid metabolism in
ESRD patients and healthy individuals [29–31]. The
method involves the use of a primed, constant infusion
of tracer methionine, containing a 13C-carboxyl and a
2
H3 methyl label. The methyl label is removed during
methionine transmethylation and the carboxyl label
appears as labelled CO2 after transsulphuration and
oxidation of homocysteine. At isotopic steady-state,
the whole body fluxes of transmethylation, transsul-
phuration and remethylation can be estimated from
sample enrichments at plateau. The main findings of the
experiments were that total remethylation and trans-
methylation flux were decreased in ESRD patients,
whereas transsulphuration rate was similar compared
with the values of the control subjects [29–31]
(Figure 2). The observation that total transsulphura-
tion was not affected in ESRD, is probably the result
of a similar dietary protein and therefore, methionine
intake in both groups. Two mechanisms may explain
the elevated plasma homocysteine level and decreased
flux through the methylation cycle in ESRD. First, the
primary defect in the sulphur amino acid metabolism
may be an impairment of homocysteine transsulphura-
tion, which is offset by a higher plasma homocysteine
after which the daily methionine load can again be
metabolized through the transsulphuration pathway.
The higher homocysteine level would slow down the
methylation cycle by inhibiting transmethylation.
Second, the primary defect may be a block in
1164
homocysteine remethylation, which can only be
partially compensated for by an increase in plasma
homocysteine, resulting in a further slowing down of
the methylation cycle without compromising trans-
sulphuration. In the latter model, the elevated cysteine
levels and the more favourable response to folate
compared with vitamin B6 therapy in ESRD may be
better explained. To reconcile the observations of
a close relationship between homocysteine and GFR
on the one hand and a primary defect in remethyla-
tion or transsulphuration on the other hand, it can
be hypothesized that an unknown compound, which
is eliminated by glomerular filtration, regulates
homocysteine clearance by remethylation or trans-
sulphuration.
Consequences of hyperhomocysteinaemia
Several biochemical mechanisms have been proposed
to explain the presumed vasculotoxic effects of homo-
cysteine. The main theory is that high homocysteine
levels lead to endothelial dysfunction. Impaired
endothelial vasomotor responses have been ascribed
to a reduced bioavailability of nitric oxide due to auto-
oxidation of homocysteine in plasma which leads to
oxidative inactivation of nitric oxide [32]. Alternatively,
homocysteine may lead to the accumulation of
asymmetric dimethylarginine, an endogenous inhibitor
of nitric oxide synthase, by inhibiting its catabolizing
enzyme dimethylarginine dimethylaminohydrolase.
In patients with renal insuffciency, hyperhomocys-
teinaemia and impaired endothelium-dependent vaso-
dilatation are both present, but are not significantly
related to each other [33–35]. In another study, there
was no significant relationship between plasma homo-
cysteine and antibodies against oxidized LDL, a marker
of oxidative stress, in haemodialysis patients [36].
Other potential consequences of hyperhomo-
cysteinaemia include general hypomethylation due to
inhibition of the transmethylation pathway, post-
translational protein modification and/or damage by
homocysteine-thiolactone, a highly reactive com-
pound formed by methionyl-tRNA synthetase, and
enhanced endoplasmic reticulum stress, which involves
disruption of the folding and the processing of the
newly synthesized proteins in the endoplasmic
reticulum.
Homocysteine-lowering treatment
From the many, mostly short-term, homocysteine-
lowering intervention studies in renal failure patients,
one can conclude that folate compounds are the most
effective and consistent in lowering plasma homocys-
teine compared with other therapies. Although direct
comparisons are scarce, the maximal homocysteine-
reducing capacity of folic acid in dialysis patients seems
to have already reached a low dose (1–2 mg daily)
[37–39]. Vitamin B6 does not seem to have a significant
Nephrol Dial Transplant (2006) 21: Editorial Comments
impact on plasma homocysteine levels in dialysis
patients, whereas vitamin B12 may lower homocysteine
somewhat further when added to folic acid, especially
in patients with subclinical B12 deficiency. Other
therapies that have been tested (with moderate success
at best) include supplementation of betaine, serine,
creatine or acetylcysteine and dialysis with superflux
or protein leaking filters. A common finding of all
intervention studies is that final on-treatment homo-
cysteine levels remain above normal in the majority of
patients.
Surprisingly, most studies have examined the effect
of homocysteine-lowering treatment only on plasma
homocysteine itself (or related metabolites). The
influence of homocysteine-lowering treatment on vas-
cular or other pathogenic factors has been addressed
in only a few studies. We have shown that one year of
folic acid therapy in haemo- and peritoneal dialysis
patients did not improve carotid artery stiffness or
Downloaded from http://ndt.oxfordjournals.org/ by guest on September 24, 2015
endothelial dysfunction, which was assessed as flow-
mediated vasodilatation in the brachial artery and
with biochemical markers [37,38,40]. Subsequently, it
was also shown that folic acid therapy did not improve
endothelium-dependent vasodilatation in patients
with pre-dialysis renal failure [35]. Using the stable
isotope method with labelled methionine, we have
shown that folic acid treatment normalizes transmethyl-
ation and remethylation fluxes in haemodialysis
patients, in spite of a persistent elevation of plasma
homocysteine [31]. Ingrosso et al. [41] demonstrated
that folate treatment in ESRD patients ameliorates
DNA hypomethylation and restores altered expression
of genes that depend on DNA methylation, again
without normalization of plasma homocysteine.
Together, these interesting findings suggest that folate
therapy may have biological effects in ESRD patients
which are not mediated by the lowering of plasma
homocysteine per se, but rather by the improvement of
the transmethylation pathway, in which many impor-
tant methylation reactions take place [42].
So far, only one prospective randomized intervention
trial in renal patients with clinical endpoints has been
published [6]. In this study, 510 ESRD patients (mostly
on haemodialysis) were randomized to 1, 5 or 15 mg
folic acid daily. After a mean follow-up of 2 years, there
was no significant difference in mortality or cardiovas-
cular events between the three groups. Beneficial effects
of homocysteine-lowering, however, cannot yet be
excluded because there was no true placebo group in
this study. Currently, there are two other clinical
endpoint trials underway in patients with chronic
kidney disease. In the FAVORIT trial, about 4000
renal transplant recipients will be randomized to
a combination of folate, vitamin B12 and vitamin B6
or placebo, and in the HOST trial, more than 2000
patients with advanced renal disease are randomized
to a high dose of a combination of folate, vitamin B12
and vitamin B6 or to placebo [43].
In conclusion, there is no clear evidence that
homocysteine-lowering treatment with folic acid at
higher doses than 1 mg per day will lower the risk of
Nephrol Dial Transplant (2006) 21: Editorial Comments
vascular events or mortality in patients with ESRD.
The ongoing trials will hopefully further clarify the
value of homocysteine-lowering treatment in chronic
kidney disease. Further research on the effects of
an improved transmethylation by folic acid beyond
vascular biology is also warranted.
Conflict of interest statement. None declared.
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doi:10.1093/ndt/gfl089
Advance Access publication 7 March 2006
Vascular calcification—a matter of damage limitation?
Catherine M. Shanahan
Division of Cardiovascular Medicine, University of Cambridge, Box 110, Addenbrooke’s Hospital,
Hills Road, Cambridge CB2 2QQ, UK
Keywords: atherosclerosis; bone; calcification;
Fetuin-A; matrix Gla protein;
vascular smooth muscle cell; vesicles
Introduction
Vascular calcification has now been recognized as
an important determinant of cardiovascular mortality
in patients on dialysis. Recent cell biological studies,
using phenotypically modulated, human vascular
smooth muscle cells (VSMCs) in vitro, have highlighted
the importance of vascular damage, leading to vesicle
release, combined with loss of function of inhibitory
proteins, as the major events in the calcification process.
VSMC calcification is a regulated process, therefore
the potential exists to inhibit progression or more
significantly, induce regression. Identification of
damage-inducing agents and calcification inhibitors
Correspondence and offprint requests to: Dr Catherine Shanahan,
Department of Medicine, Division of Cardiovascular Medicine,
ACCI, Level 6, Box 110, Addenbrooke’s Hospital, Hills Road,
Cambridge CB2 2QQ, UK. Email: cs131@mole.bio.cam.ac.uk
ß The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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Nephrol Dial Transplant (2006) 21: Editorial Comments
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Received for publication: 30.11.05
Accepted in revised form: 24.1.06
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is now quite advanced. The next challenge will be in
determining ways to limit damage and induce expres-
sion and/or efficacy of inhibitors. Although new
therapeutics have shown the potential to act on these
pathways, there is still much to be learnt about how the
complex ‘uraemic’ milieu appears to favour vascular
calcification at the expense of bone mineralization.
Vascular calcification—two sites
with different consequences
Vascular calcification or ‘hardening of the arteries’
has long been recognized as a complication of ageing
and disease, yet until recently, little attention was paid
to its clinical consequences. However, with the realiza-
tion that vascular calcification is a time-dependent and
widespread complication of patients on dialysis, and
most likely contributes to their high cardiovascular
mortality, much attention has now been focused on its
aetiology, consequences and mechanisms [1,2].
Vascular calcification occurs at two anatomical sites
in the vessel wall, the media and the intima. Dialysis
patients have an increased prevalence of both forms,
however, it is the extreme medial calcification that is