Bernd Hohenstein

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Lipoprotein(a) in nephrological patients

DOI 10.1007/s11789-017-0086-z
Clin Res Cardiol Suppl (2017) (Suppl) 12:27–30
Lipoprotein(a) in nephrological patients
Bernd Hohenstein1,2
Published online: 8 February 2017
© The Author(s) 2017. This article is available at SpringerLink with Open Access.
Abstract In contrast to existing EAS/ESC guidelines on
the management of lipid disorders, current recommenda-
tions from nephrological societies are very conservative and
restrictive with respect to any escalation of lipid lowering/
statin therapy. Furthermore, lipoprotein(a) (Lp(a)) – an es-
tablished cardiovascular risk factor – has not even been
mentioned. While a number of retrospective and prospective
studies suggested that Lp(a) has relevant predictive value
and might have – at least in stage-3 chronic kidney dis-
ease (CKD) – the same negative effects if draged along
in non-CKD patients, there is no guidance on diagnostic
or therapeutic procedures. The persistent lack of recog-
nition automatically leads to therapeutic nihilism, which
might pose a number of relatively young patients to a sig-
nificantly increased risk for adverse cardiovascular events.
Further evaluation of Lp(a) in CKD is very important to
provide appropriate treatment to patients with high Lp(a)
levels, even in the presence of CKD.
Keywords Lipoprotein(a) · Kidney disease ·
Cardiovascular risk · Lipids
This article is part of the special issue “Lp(a) – the underestimated
cardiovascular risk factor”.
 Bernd Hohenstein
hohenstein@nephrologie-vs.de
1 Nephrological Center Villingen-Schwenningen,
Albert-Schweitzer-Str. 6, 78052 Villingen-Schwenningen,
Germany
2 Faculty of Medicine Carl Gustav Carus,
Fetscherstraße 74, 01307 Dresden, Germany
Current guidance and controversies in lipidology
versus nephrology
With the introduction of new drugs targeting proprotein
convertase subtilisin kexine type 9 (PCSK9), the effective,
target-oriented treatment of lipid disorders received a new
perspective [1, 2]. While the IMPROVE-IT trial clearly
demonstrated that “even lower” is “even better”, thereby
proving the concept of targeting LDL-C values of 70 mg/dL
(1.8 mmol/L) or lower in cardiovascular high-risk patients
[3], the new drugs will offer the chance of reaching this
target in the vast majority of patients [4].
Recent guidelines from the European Societies of Car-
diology (ESC) and Atherosclerosis (EAS) recommend –
based on the overall cardiovascular risk – that patients
with a moderately reduced eGFR of 60–30 ml/min/1.73 m2
should be classified as high-risk and with a eGFR be-
low 30 ml/min/1.73 m2 as very high-risk patients [5]. While
these guidelines recommend a strict to target reduction of
LDL-C levels, current Kidney Disease Improving Global
Outcomes (KDIGO) clinical practice guidelines for lipid
management in chronic kidney disease (CKD) do not see
evidence beyond the single-point evaluation of a patient’s
lipid status, including total cholesterol, LDL-cholesterol,
HDL-cholesterol and triglycerides, followed by a fire-and-
forget strategy [6]. European best practice guidelines fur-
ther restrict the LDL-C lowering treatment to patients with
diabetes mellitus [7].
In contrast to ESC and EAS, KDIGO recommendations
are mainly based on results from the three major interven-
tional trials in patients on dialysis and suffering from CKD:
4D, AURORA and SHARP [8–10]. While these results sug-
gest statin treatment as a primary prevention in patients with
moderate and advanced CKD [10], statins have now proven
efficacy for secondary prevention in dialysis patients [8, 9].
K
28 B. Hohenstein
Results in dialysis patients are most likely related to the
different pathophysiology developing during CKD, shift-
ing the dominance of classical cardiovascular (CV) risk
factors towards CKD related factors such as hyperphos-
phatemia, increased calcium-phosphate product, secondary
hyperparathyroidism, and a lack of calcification inhibiting
factors finally leading to more pronounced media sclerosis
and vascular stiffness [11].
So far, existing nephrological guidelines do not even rec-
ommend the measurement of Lipoprotein (a) (Lp(a)).
Lipoprotein (a) levels in kidney patients
Starting in the early 90s, a number of studies investigated
the potential role of Lp(a) in CKD patients. As depicted by
Kronenberg and colleagues, it is clear that Lp(a) levels start
to rise with decreasing glomerular filtration rate (GFR) be-
ing fourfold higher in patients with nephrotic range protein-
uria compared to healthy controls [12]. This is completely
corrected in kidney transplant patients and partially reduced
in patients on hemodialysis and to a lesser extent also in
patients undergoing peritoneal dialysis.
From a pathophysiologic point of view, in-vivo studies
demonstrated that patients with nephrotic syndrome have an
increased Lp(a) synthesis rate, while hemodialysis patients
have a steady production rate in presence of a prolonged
residence time termed catabolic block [12].
Relevance of high Lp(a) in CKD
Recently, the Chronic Renal Insufficiency Cohort (CRIC)
study performed a systematic measurement of serum lipids
and lipoproteins in a CKD cohort of 3939 patients [13].
They tried to detect factors being relevant for the progres-
sion of CKD, but failed to demonstrate any associations
with lipid parameters and especially with Lp(a).
So far, most investigations focused on patients already
undergoing dialysis treatment. More than ten years ago,
the Choices for Healthy Outcomes in Caring for End-Stage
Renal Disease (CHOICE) study prospectively included in-
cident dialysis patients [14, 15]. In 864 out of 1041 a Lp(a)
measurement was performed. The investigators aimed to
answer the questions, whether small apo(a) size and/or
high Lp(a) levels predict mortality or CV events in dial-
ysis patients. While they found that small apo(a) size, but
not a high Lp(a) level was predictive for mortality [14],
they later published a second study stating that high Lp(a)
levels as well as small apo(a) size can predict CV events in
dialysis patients [15]. In the later study, patients with more
than 22 kringle-type IV repeats and Lp(a) concentrations
of more than 123 nmol/L (4th quartile) had a 1.73 fold risk
for CV events (p < 0.0005). While experimental data in
uremic mice pointed into the same direction [16], further
confirming studies in CKD have not been performed until
today.
More recently, investigators from Japan evaluated 904
patients with CKD out of 3508 patients undergoing a percu-
taneous coronary intervention (PCI) [17]. The comparison
between high (n = 454) and low (n = 450) Lp(a) levels re-
garding all-cause death and acute coronary syndrome over
a period of 4.7 years found a worse outcome in those with
higher Lp(a) levels. Lp(a) seemed to be an independent
predictor of adverse outcomes in CKD patients following
PCI.
Finally, Kollerits and colleagues performed a post-hoc
analysis of patients participating in the 4D study which
included type 2 diabetics undergoing hemodialysis either
treated with 20 mg of atorvastatin or placebo [18]. 1233 out
of 1255 initial samples were available and measurement of
Lp(a) was performed at baseline and after 6 months. The
authors divided patients according to their Lp(a) levels as
well as low and high molecular weight isoforms into quar-
tiles. Increased Lp(a) concentrations were associated with
all-cause mortality, but this effect was mainly driven by
infections. This Lp(a) related effect was especially promi-
nent in younger patients (<66 years of age), which also had
a higher risk of fatal stroke (hazard ratio 1.54; P = 0.03).
At least in part, these studies confirmed two earlier find-
ings published by Kronenberg and colleagues investigat-
ing the relevance of Lp(a) for the development of coronary
artery disease and carotid atherosclerosis in end-stage renal
disease patients more than 20 years ago [19, 20].
In both studies low molecular weight Lp(a) isoforms was
associated with more severe atherosclerotic changes. While
Lp(a) concentrations were not linked with CAD, they as-
sociated with carotid atherosclerosis and the number of af-
fected vascular beds.
Of note, all these publications widely reflect patients hav-
ing moderately increased Lp(a) levels below the currently
accepted threshold of 120 nmol/L or 60 mg/dL indicating
the necessity of lipoprotein apheresis according to the Ger-
man Federal Joint Committee [21].
Conclusions from existing literature
In summary, a number of prospective studies pointed to-
wards a relevance of Lp(a) as relevant CV risk factor in
CKD and dialysis patients predicting both, the develop-
ment of atherosclerotic lesions and adverse outcomes. Even
though CKD related vascular pathology becomes more rele-
vant in advanced stages of CKD, it is very likely that Lp(a) –
as in non-CKD individuals – significantly contributes to the
development and progression of atherosclerotic lesions. Yet,
K
Lipoprotein(a) in nephrological patients 29
Fig. 1 Proposed handling of
lipid disorders in CKD incl.
Lp(a). * 2.6 mmol/L; # 1.8
mmol/L; § 120 nmol/L; LA
= lipoprotein apheresis; ‡ us-
ing atorvastatin, simvastatin/
ezetemibe, rosuvastatin, or
atorvastatin/ezetimibe, and/or
PCSK9i
it is unclear to which extent very high Lp(a) levels (above
the 90% percentile) will influence CAD in CKD patients.
Especially in moderate CKD, it seems to be important to
carefully evaluate traditional risk factors including Lp(a)
and take this into consideration and treatment decisions.
Clearly, further studies in CKD patients are necessary, but
momentary nihilism will not prevent any adverse event.
Dealing with high Lp(a) in daily clinical practice
Especially in early stages of CKD, Lp(a) should be mea-
sured in every patient since the CKD-related increase will
be limited in these patients and less controversies on the
role of decreased eGFR will occur. CV events in CKD
stage 3 patients at the age of 50–55 or below in presence of
significantly elevated Lp(a) levels should not be primarily
accepted as a consequence of CKD, but undergo intensive
workup of all vascular beds (carotids, peripheral vessels,
coronaries, aorta) and aggressive treatment. According to
the accepted German guidelines [21], lipoprotein apheresis
should be initiated in patients with progressive CV disease
and Lp(a) levels of more than 60 mg/dL (or 120 nmol/L).
Individualized decisions are necessary, even more carefully
in advanced CKD. It is important to note that the relevance
of Lp(a) in patients after kidney transplantation (KTx) is
completely unclear. However, early manifestations of CV
disease at an early stage of CKD might also guide the treat-
ment decision after KTx, since CV disease is one of the
leading causes for the loss of a functioning graft. An algo-
rithm for the handling of lipid disorders including Lp(a) in
CKD is proposed in Fig. 1.
Conflict of interest Honoraria, research funding and coverage of
travel expenses by Amgen, B. Braun Avitum, Fresenius Medical Care,
Kaneka, Miltenyi Biotec, Sanofi.
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted
use, distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a
link to the Creative Commons license, and indicate if changes were
made.
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