Like blood pressure and cholesterol, hoocysteine shows a paradoxical inverse relationship with cardiovascular complications in end-stage renal disease (ESRD). A paper by Ducloux et al. in this issue adds perhaps decisive evidence on malnutrition-hypoalbuminemia as the main factor explaining the counterintuitive association between homocysteine and clinical outcome reported in previous studies

Mallamai, F.

Zoccali, C.

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204   Kidney International (2006) 69
commentar y
See original article on page 331
http://www.kidney-international.org
© 2006 International Society of Nephrology
Homocysteine and risk in end-stage 
renal disease: a matter of context
C Zoccali1 and F Mallamaci1
Like  blood pressure and cholesterol, hoocysteine shows a paradoxical 
inverse relationship with cardiovascular complications in end-stage 
renal disease (ESRD). A paper by Ducloux et al. in this issue adds perhaps 
decisive evidence on malnutrition-hypoalbuminemia as the main factor 
explaining the counterintuitive association between homocysteine and 
clinical outcome reported in previous studies.
Kidney International (2006) 69, 204–206. doi:10.1038/sj.ki.5000078
Reverse epidemiology in ESRD
Th e problem of the inverse, or reverse, 
epidemiology of ESRD is one of the most 
discussed topics related to the high risk 
of death in ESRD patients. Kalantar-
Zadeh et al., in particular, have devoted 
much attention to reverse epidemiology 
in ESRD and have discussed it in a wide 
perspective.1 In general, the designation 
of ‘inverse’ or ‘reverse’ apparently alludes 
to counterintuitive, biologically unex-
pected eff ects. In reality, factual analy-
sis almost always shows that there is no 
paradox in the relationship between risk 
factors and clinical outcomes in ESRD. 
Th e problem goes beyond renal failure 
and depends on the fact that a given 
outcome may have diff erent proximate 
causes in diff erent study populations. 
In the general population without car-
diovascular complications, variables 
like BP maintain a monotonic asso-
ciation with clinical outcomes across 
a wide range of values. Starting from 
systolic BP values as low as 110 mm Hg, 
the higher the systolic BP, the higher the 
risk of cardiovascular events.2 Th is is a 
causal relationship, as reduction of BP by 
pharmacological or non-pharmacologi-
cal (for example, salt intake reduction) 
interventions determines a proportional 
decrease in event rate. However, neither 
the strength of this relationship in the 
general population nor the undisputed 
efficacy of antihypertensive agents in 
preventing cardiovascular disasters 
should be taken as evidence that higher 
BP values always refl ect a condition of 
proportionally higher risk. It is only in 
the population in which this relationship 
was observed that we should expect pro-
gressively higher BP values to be accom-
panied by a parallel risk increase. If we 
examine the same problem in patients 
with heart failure, the association is 
inverse rather than direct, because in this 
condition it is not hypertension but low 
BP (the result of ventricular pump fail-
ure and a surrogate of inadequate organ 
perfusion) that marks and determines a 
high risk of death (Figure 1). Th is con-
cept is further highlighted by the fact 
that not only high systemic BP but also 
high pulmonary pressure predict better 
outcomes in high-risk patients.3 Indeed, 
in pulmonary hypertension, the death 
rate is higher in patients with relatively 
lower pulmonary pressure than in those 
with relatively higher values, because in 
this particular setting, relatively lower 
pulmonary pressure reflects a more 
severe degree of right ventricular systo-
lic dysfunction. Th e fact that the same 
variable has opposite relationships with 
the same clinical outcome has long been 
considered a puzzling, paradoxical phe-
nomenon. However, there is no para-
dox in an inverse relationship between 
systemic or pulmonary BP and death 
in patients with heart failure or pulmo-
nary hypertension; this is just what we 
expect on the basis of pathophysiological 
knowledge. In clinical practice, no doc-
tor questions the fact that two diff erent 
interventions for arterial pressure are 
required in subjects with uncomplicated 
hypertension and in patients with heart 
failure. In subjects with uncomplicated 
hypertension, BP should be lowered to 
reduce left  ventricular overload, and, 
conversely, in patients with compro-
mised left  ventricular systolic function, 
BP should be increased by interven-
tions that directly or indirectly amelio-
rate ventricular performance. Similar 
problems exist with serum cholesterol. 
Cholesterol is directly related to cardio-
vascular outcomes in the general popula-
tion. In contrast, in high-risk conditions 
characterized by high C-reactive protein 
(a measure of systemic infl ammation), 
such as stroke, heart failure, and coro-
nary heart disease, the relationship is J- 
or U-shaped. Again there is no paradox 
in this fi nding, because low cholesterol 
is just an element of the complex patho-
physiological response to infl ammation. 
In other words, in patients with severe 
cardiovascular complications, low cho-
lesterol becomes a marker of the severity 
of infl ammation, that is, of the ultimate 
event driver of these conditions. Th us it 
is no surprise that arterial pressure and 
cholesterol are inversely rather than 
directly related to clinical outcomes in 
a high-risk, relatively old population 
such as the ESRD population. In fact, 
Liu et al.4 have nicely demonstrated 
that, in a well-selected incident cohort 
of dialysis patients without evidence 
of infl ammation (C-reactive protein < 
10 mg/dl), the risk of death was 3.2 times 
higher in patients with high cholesterol 
(>240 mg/dl) than in those with low 
cholesterol (<160 mg/dl), whereas, in 
the control cohort composed of patients 
with infl ammation (C-reactive protein > 
1Istituto di Biomedicina–Epidemiologia e 
Fisiopatologia Clinica delle Malattie Renali e 
dell’Ipertensione Arteriosa e Unità Operativa di 
Nefrologia, Dialisi e Trapianto Renale, Ospedali 
Riuniti, Reggio Calabria, Italy
Correspondence: C Zoccali, Istituto di 
Biomedicina–Epidemiologia e Fisiopatologia 
Clinica delle Malattie Renali e dell’Ipertensione 
Arteriosa e Unità Operativa di Nefrologia, Dialisi 
e Trapianto Renale, Ospedali Riuniti, Reggio 
Calabria, Italy. Email: carmine.zoccali@tin.it
Kidney International (2006) 69       205
commentar y
10 mg/dl), the death risk was 38% lower 
in patients with high cholesterol.
Hyperhomocysteinemia and clinical 
outcomes in ESRD
Hyperhomocysteinemia is another risk 
factor considered as a puzzling prob-
lem in ESRD.5 To date, six prospective 
cohort studies have examined the rela-
tionship between the plasma concentra-
tion of homocysteine on the one hand, 
and death and atherosclerotic complica-
tions on the other hand, in patients with 
ESRD, and the results are disparate. It 
is worth noting that the study by Mal-
lamaci et al.,6 which reported a positive 
association, did not include patients with 
heart failure, a condition notoriously 
characterized by severe infl ammation. 
Furthermore, it appears to be of fore-
most importance that more than 70% 
of circulating homocysteine is disulfi de-
bonded to protein, mostly to albumin.7 
Adjustment for serum albumin was per-
formed in the (positive) study by Mal-
lamaci et al., whereas no such adjustment 
was performed in the (negative) study by 
Suliman et al.8 In a more recent study by 
Kalantar-Zadeh et al., adjustment for 
albumin rendered largely insignifi cant 
the apparent (unadjusted) inverse asso-
ciation between this sulfur amino acid 
and hospitalization and death.9 Regard-
less of the analytical strategy adopted in 
these studies, there was no interpretative 
disagreement among authors report-
ing positive and negative associations. 
Suliman et al. commented that “the 
paradoxical reverse association between 
homocysteine and clinical outcome in 
ESRD patients does not, as such, refute 
a possible role for homocysteine in the 
vascular pathogenesis”; and Kalantar-
Zadeh et al. added, “Th e positive correla-
tion between homocysteine and markers 
of protein-energy nutritional status…
may partially, but not fully, explain the 
paradoxical association between homo-
cysteine and mortality.” Th us, negative 
associations — rather than negating 
homocysteine vasculotoxicity — most 
likely refl ect the highly deleterious eff ects 
of infl ammation and malnutrition. Th e 
study by Ducloux et al. in this issue of 
KI10 adds perhaps decisive evidence on 
malnutrition-associated hypoalbumine-
mia as an important confounder in the 
interpretation of the eff ect of circulating 
homocysteine on death and cardiovas-
cular events in ESRD. Indeed, as in the 
above-mentioned study by Liu et al. deal-
ing with serum cholesterol,4 Ducloux et 
al. found that homocysteine tended to 
be inversely related to all-cause death 
rate in infl amed, malnourished patients 
(third versus fi rst homocysteine tertile, 
relative risk = 0.78 (95% confidence 
interval: 0.47–01.02)) but that it showed 
an opposite association with the same 
outcome in well-nourished, uninfl amed 
dialysis patients (relative risk = 1.55 (95% 
confi dence interval: 1.12–4.72)). Genetic 
epidemiology provides additional evi-
dence that hyperhomocysteinemia is a 
potential driver of cardiovascular events 
in ESRD patients. At variance with stud-
ies based on the measurement of plasma 
homocysteine — an indicator infl uenced 
by both environmental and genetic fac-
tors — studies based on genetic markers 
of hyperhomocysteinemia are not con-
founded by environmental factors infl u-
encing plasma homocysteine.11 In this 
regard it is interesting to note that in a 
survey of dialysis patients, homocysteine 
was negatively associated with past car-
diovascular complications, whereas these 
events maintained a positive association 
with the TT genotype of the C677T pol-
ymorphism of the MTHF gene (a gene 
variant that determines an increase in 
plasma homocysteine).12 By the same 
token, in another survey aimed at explor-
ing potential predictors of arterio-fi stula 
thrombosis, a positive association was 
reported between this polymorphism 
and arteriovenous fi stula outcome.13
What we need now: multifactorial inter-
vention studies
At this stage, we are faced with the 
problem of performing well-powered 
intervention studies aimed at establish-
ing whether lowering plasma homo-
cysteine produces benefi cial eff ects in 
dialysis patients. Trials based solely on 
folic acid are probably inadequate to test 
the hypothesis, because folic acid low-
ers but largely fails to normalize plasma 
homocysteine in ESRD14 and leaves the 
problem of malnutrition lurking in the 
background. Perhaps the best approach 
is a multifactorial intervention target-
ing malnutrition, infl ammation, hyper-
homocysteinemia, and oxidative stress. 
In this regard, acetylcysteine appears 
to be a promising drug.15 Indeed, when 
given intravenously during dialysis, this 
antioxidant safely brings plasma homo-
cysteine levels into the normal range and 
produces an improvement in endothelial 
dysfunction. Long-term administration 
of this drug reduced cardiovascular-event 
rate in ESRD patients16 in the sole study 
available so far. Th e study by Ducloux et 
al.10 makes a strong call for intervention 
studies in ESRD. Th e exceedingly high 
cardiovascular mortality of patients with 
ESRD makes such studies not only sci-
entifi cally important but also ethically 
mandatory if we are to curb this problem 
on which very little therapeutic progress 
has been made so far.
REFERENCES
1 Kalantar-Zadeh K, Block G, Humphreys 
MH, Kopple JD. Reverse epidemiology of 
cardiovascular risk factors in maintenance 
dialysis patients. Kidney Int 2003; 63: 793–808.
2 Lewington S, Clarke R, Qizilbash N et al. Age-
specific relevance of usual blood pressure to 
vascular mortality: a meta-analysis of individual 
data for one million adults in 61 prospective 
studies. Lancet 2002; 360: 1903–1913.
3 McLaughlin VV, Sitbon O, Badesch DB et al. 
Survival with first-line bosentan in patients with 
primary pulmonary hypertension. Eur Respir J 
2005; 25: 244–249.
4 Liu Y, Coresh J, Eustace JA et al. Association 
between cholesterol level and mortality in 
dialysis patients: role of inflammation and 
malnutrition. JAMA 2004; 291: 451–459.
5 Suliman ME, Barany P, Kalantar-Zadeh K et 
Figure 1 |  Long-term relationship among 
systolic pressure, left ventricular mass, 
and death rate in the dialysis population.  
Persistent hypertension (along with other 
factors) generates and progressively 
aggravates left ventricular hypertrophy up 
to a point where heart failure supervenes. 
Heart failure lowers blood pressure (BP) and 
eventually causes death, thus generating an 
inverse association between BP and mortality. 
Death rate
Systolic BPmm Hg
180
100
Heart failure
Left
ventricular
mass
Persistent 
hypertension
206   Kidney International (2006) 69
commentar y
al. Homocysteine in uraemia: a puzzling and 
conflicting story. Nephrol Dial Transplant 2005; 20: 
16–21.
6 Mallamaci F, Zoccali C, Tripepi G et al. 
Hyperhomocysteinemia predicts cardiovascular 
outcomes in hemodialysis patients. Kidney Int 
2002; 61: 609–614.
7 Majors AK, Sengupta S, Willard B et al. 
Homocysteine binds to human plasma 
fibronectin and inhibits its interaction with fibrin. 
Arterioscler Thromb Vasc Biol 2002; 22: 1354–1359.
8 Suliman ME, Qureshi AR, Barany P et al. 
Hyperhomocysteinemia, nutritional status, and 
cardiovascular disease in hemodialysis patients. 
Kidney Int 2000; 57: 1727–1735.
9 Kalantar-Zadeh K, Block G, Humphreys MH 
et al. A low, rather than a high, total plasma 
homocysteine is an indicator of poor outcome in 
hemodialysis patients. J Am Soc Nephrol 2004; 15: 
442–453.
10 Ducloux D, Klein A, Kazory A et al. Impact of 
malnutrition-inflammation on association 
between homocysteine and mortality in 
hemodialysis patients. Kidney Int 2006; 69: 
331–335. 
11 Zoccali C, Testa A, Spoto B et al. Mendelian 
randomization: a new approach to studying 
epidemiology in ESRD. Am J Kidney Dis 2006 (in 
press)
12 Wrone EM, Zehnder JL, Hornberger JM et al. An 
MTHFR variant, homocysteine, and cardiovascular 
comorbidity in renal disease. Kidney Int 2001; 60: 
1106–1113.
13 Fukasawa M, Matsushita K, Kamiyama M et al. 
The methylentetrahydrofolate reductase C677T 
point mutation is a risk factor for vascular access 
thrombosis in hemodialysis patients. Am J Kidney 
Dis 2003; 41: 637–642.
14 Wrone EM, Hornberger JM, Zehnder JL et al. 
Randomized trial of folic acid for prevention of 
cardiovascular events in end-stage renal disease. J 
Am Soc Nephrol 2004; 15: 420–426.
15 Scholze A, Rinder C, Beige J et al. Acetylcysteine 
reduces plasma homocysteine concentration 
and improves pulse pressure and endothelial 
function in patients with end-stage renal failure. 
Circulation 2004; 109: 369–374.
16 Tepel M, van der Giet M, Statz M et al. The 
antioxidant acetylcysteine reduces cardiovascular 
events in patients with end-stage renal failure: 
a randomized, controlled trial. Circulation 2003; 
107: 992–995.
See original article on page 336
Inflammation and dyslipidemia in 
nephropathy: an epidemiologic 
perspective
SL Seliger1
The association of dyslipidermia and inflammatory markers 
with decreased renal function has been reported in several large 
epidemiologic studies. In this issue, Lin et al examine these associations 
among middle-aged and older type 2 diabics, a population at high risk 
for chronic kidney disease. Their findings support a role for these factors 
in the pathogenesis of progressive renal disease.
Kidney International (2006) 69, 206–208. doi:10.1038/sj.ki.5000111
Th e crucial role of dyslipidemia in the pro-
gression of proteinuric kidney disease was 
fi rst described systematically more than 20 
years ago by Moorhead et al.1,2 Th ey pro-
posed a model in which quantitative and 
qualitative changes in circulating lipopro-
teins, representing metabolic responses 
to proteinuria, result in mesangial-cell 
injury, activation, and proliferation, as 
well as injury to glomerular epithelial 
cells and basement membrane. Th e result-
ing cellular injury and activation in turn 
lead to excess production of extracellular 
matrix and progressive glomerulosclero-
sis. Concurrently, accelerated atheroscle-
rosis induced by the hyperlipidemia, and 
progressive tubulo-interstitial fi brosis as 
a reaction to reabsorption of fi ltered lipo-
proteins, contribute to the global nephro-
sclerosis process, resulting ultimately in 
chronic renal failure.
1University of Maryland School of Medicine, 
Department of Medicine, Baltimore, Maryland, USA
 Correspondence: SL Seliger, University of 
Maryland School of Medicine, Department of 
Medicine, 22 S. Greene Street, N3W143, Baltimore, 
Maryland 21201, USA. Email: sseliger@medicine.
umaryland.edu
Since the publication of this hypoth-
esis, a considerable body of evidence 
from in vitro and in vivo animal model 
experiments has supported this model 
of progressive renal injury. Th ese stud-
ies have also revealed the importance 
of an intermediate infl ammatory proc-
ess in contributing to the progressive 
nephrosclerosis. Th is infl ammation is 
characterized histologically by a mono-
cyte/macrophage infi ltrate and at the 
molecular level by increased production 
of chemokines including tumor necrosis 
factor-α, RANTES, vascular cell adhe-
sion molecule, and intercellular adhe-
sion molecule. Central to this model 
of lipid nephrotoxicity mediated by 
monocytic infl ammation is the concept 
of a positive-feedback loop, in which 
the progressive mesangial, epithelial, 
and tubulo-interstitial injury results in 
worsening proteinuria and renal fi ltra-
tion function, which in turn lead to more 
severe dyslipidemia and infl ammation. 
Moorhead termed this feedback loop the 
“lipoprotein injury cycle.”2
Th e implication of these fi ndings from 
experimental models is that one could 
prevent or at least attenuate the process 
of progressive nephrosclerosis through 
interventions aimed at certain mediators 
of this cycle. However, it has not been 
clear whether these lipid and infl am-
matory factors are important in the 
development and progression of diverse 
forms of human kidney disease. Except 
for very rare inherited defi ciencies of 
lipoprotein metabolism, humans with 
isolated dyslipidemia but without other 
risk factors do not generally develop pro-
gressive glomerulosclerosis, in contrast 
to the experimental models described 
by Moorhead et al. and others. On the 
other hand, it is entirely plausible that 
in the setting of primary renal disease or 
systemic conditions known to injure the 
kidney (for example, sustained hypergly-
cemia or systemic hypertension), these 
factors play a major role in the initiation 
and progression of kidney disease.
However, there are considerable meth-
odological challenges to demonstrating 
these effects in large, heterogeneous 
human populations. As with all obser-
vational epidemiologic research, the 
accurate ascertainment of exposures and 


Homocysteine and risk in end-stage renal disease: a matter of context 

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Homocysteine and risk in end-stage renal disease: a matter of context

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