European Heart Journal (2023) 00, 1–3 EDITORIAL

https://doi.org/10.1093/eurheartj/ehad039

The cardiovascular–renal link and the health

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burden of kidney failure
1,2,3
Carmine Zoccali * and Francesca Mallamaci4
1
Renal Research Institute, New York, NY, USA; 2Associazione Ipertensione Nefrologia e Trapianto Renale (IPNET) c/o Nefrologia e CNR, Grande Ospedale Metropolitano, 89124 Reggio Calabria,
Italy; 3Institute of Biology and Molecular Genetics (BIOGEM), Ariano Irpino, Italy; and 4Nephrology and Transplantation Unit, Grande Ospedale Metropolitano and CNR-IFC, Reggio Calabria, Italy

This editorial refers to ‘Major cardiovascular events and subsequent risk of kidney failure with replacement therapy: a CKD Prognosis
Consortium study’, by P.B. Mark et al., https://doi.org/10.1093/eurheartj/ehac825.

Graphical Abstract

Chronic kidney disease is an

exceedingly complex condition
Type
T 2 Diabetes
encompassing the highest
burden of comorbidities among
major chronic diseases

H
Hypertension Kd
Kidney ffailure
ailure
l

Cardiovascular diseases (namely

heart failure,
f ilure, coronary heart
fa

stroke) increase the risk of kidney

C d
Cardiovascular diseases er
Cancer
ffailure
fa ilure leading to dialysis or
renal transplantation; in addition
the risk deriving from lung
diseases, cancer and liver disease
all contribute to the high risk
Lungg diseases Liver diseases
f kidney fa
for ffailure
ilure

CKD may be caused by a variety of risk factors including type 2 diabetes, hypertension, neoplasia, liver diseases, and cardiovascular diseases. These
diseases are inter-related, and all contribute to causing CKD.

Systemic homeostasis requires the coordination of multiple organs and chronic diseases, including cancer, hypertension, diabetes, and liver dis-
tissues. To respond to various internal and external demands, a system eases (Graphical Abstract). In this complex scenario, CKD is the medical
of interorgan communication has been developed in higher biological condition associated with the highest number of comorbidities.3
species through which one organ can affect biological pathways in a dis- Dysregulation of the cardiovascular–kidney cross-talk is an import-
tant organ. Alterations of interorgan cross-talk can lead to various sorts ant mechanism underlying cardiovascular diseases and CKD. In unine-
of diseases, from metabolic diseases to cardiovascular and kidney dis- phrectomized rats, experimental myocardial infarction of moderate
eases. In this respect, both chronic kidney disease (CKD)1 and heart fail- degree causes focal glomerulosclerosis and proteinuria, and this alter-
ure2 are better seen as systemic diseases rather than as diseases ation is prevented by angiotensin-converting enzyme (ACE) inhibition.4
confined to a single organ. These two diseases are key parts of an inter- Similarly, in a post-myocardial infarction trial (Captopril and
acting scenario linking various components of the current epidemic of Thrombolysis Study, CATS), patients in the placebo arm had a

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
* Corresponding author. Emails: [email protected] or [email protected]
© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected]
2 Editorial

glomerular filtration rate (GFR) decline of 5.5 mL/min/year which was is expected to double in 2030. Thus, solid knowledge based on
prevented by treatment with ACE inhibitors (−0.5 mL/min/year). large-scale epidemiological information on the risk of kidney failure
Classical pathophysiological studies by Ljungman and Laragh in the due to cardiovascular diseases is a clinical research priority.
1990s clearly demonstrated that the GFR becomes flow dependent We live in the ‘big epidemiology era’. Epidemiologists worldwide join
in patients with severe heart failure5 Conversely, kidney diseases can their efforts to generate comprehensive, transnational databases pro-

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give rise to cardiac dysfunction. In two experimental models of CKD, viding accurate statistics of human diseases and their outcomes. The
reduced kidney function resulted in the expansion of cardiac macro- best known of these efforts is the Global Burden of Disease (GBD) con-
phages through a local proliferation of resident populations and sortium, an initiative aimed to measure disability and death from a
the influx of circulating monocytes.6 In the presence of a normal esti- multitude of causes worldwide. Over the past two decades, this initia-
mated GFR (eGFR), even mild albuminuria (albumin/creatinine ratio tive has grown to involve nearly 5500 investigators and produces annu-
>30 < 300 mg/g) is associated with a 2.7-fold increased risk of cardio- ally updated information. Large, detailed cardiovascular databases exist
vascular mortality.7 CKD increases the risk of atrial fibrillation and, which allow in-depth analysis of various aspects of cardiovascular ther-
vice versa, this arrhythmia portends a high risk of subsequent renal apeutics. The Swedish Angiography and Angioplasty Registry (SCAAR)
function decline in CKD patients.8 Vascular disease in CKD manifests enrolled all coronary interventional procedures performed in Sweden
as accelerated atherosclerosis, vascular calcification, abnormal myocar- since 2005 with the registration of stent thrombosis in every patient
dial remodelling, and ventricular hypertrophy.9 A variety of factors undergoing subsequent coronary angiographies for all previously per-
elicited by kidney damage and/or dysfunction—from inflammation to cutaneous coronary intervention (PCI)-treated lesions. By using this da-
sympathetic overactivity, endogenous inhibitors of the nitric oxide sys- taset, the occurrence of stent thrombosis in specific PCI settings could
tem, and bone mineral disorders—give rise to uniquely severe coron- be investigated, and analyses in SCAAR have already provided funda-
ary, peripheral, and cerebrovascular disease in CKD patients.1 mental evidence on drug-eluting stent performance. By the same token,
Cerebral ischaemia by middle cerebral artery ligation results in podo- large-scale data collection via remote monitoring was done in
cyte damage and proteinuria in an experimental model in the rat. ALTITUDE, a study that registered survival in patients with implantable
Stroke may lead to kidney dysfunction and vice versa, and this bidirec- cardioverter-defibrillator (ICD) and cardiac resynchronization therapy-
tional link can adversely impact the functional and structural integrity of defibrillator (CRT-D) devices across the USA, and MERLIN, a study that
the kidney and the cerebrovascular system.10 investigated the relationship between the level of adherence to auto-
The relationship between cardiovascular disease and the risk of kid- matic wireless remote monitoring and survival in pacemaker and defib-
ney dysfunction and progression toward kidney failure is an issue of ut- rillator patients. Data on heart failure patients undergoing remote
most clinical relevance which has been intensively investigated over the monitoring after cardiac resynchronization therapy are being collected
last three decades. Kidney failure requiring renal replacement treat- in Germany and, on a world-wide scale, millions of patients can be re-
ment (KF-RRT) is considered the gold standard endpoint in clinical gistered in international databases in the next years. Eventually, analyses
studies dealing with kidney diseases.11 Various surrogates of this of these data are expected to improve heart failure disease progression
endpoint exist but, however good, these surrogates remain inherently and survival.
inferior to the gold standard. In the Stockholm CREAtinine For various reasons, nephrology has lagged behind in the creation of
Measurements (SCREAM) project, Ishigami et al. examined the slopes large-scale consortia collecting information on renal diseases. A notable
of eGFR decline in the 2 years before vs. after an incident hospitalization exception is the Chronic Kidney Disease Epidemiology Collaboration
with heart failure, coronary heart disease, and stroke. In this study, (CKD-EPI). This consortium includes research cohorts and health sys-
heart failure and coronary heart disease, but not stroke, were signifi- tem datasets from 41 countries in North America, Europe, the Middle
cantly associated with a subsequent accelerated decline in eGFR.12 East, Asia, and Australia. Cohorts included in the CKD-EPI collabor-
The sole study that looked at the same issue by adopting the gold stand- ation encompass screening cohorts, high-risk cohorts (e.g. diabetes),
ard endpoint, KF-RRT, is an analysis by the same author based on the and CKD cohorts. Globally >30 million individuals with CKD are regis-
Atherosclerosis Risk in Communities (ARIC) database.13 Remarkably, tered in this database. In this issue of the European Heart Journal, Patrick
when cardiovascular risk factors were modelled in isolation in adjusted Mark and colleagues15 make treasure of the CKD-EPI consortium
models including the GFR and proteinuria, the risk for KF-RRT by heart database to perform detailed analyses of the relationship between car-
failure was the highest [hazard ratio (HR) = 11] followed by coronary diovascular diseases and the incident risk of KF-RRT, i.e. the gold stand-
heart disease (HR = 3.7), atrial fibrillation (HR = 2.7), and stroke ard clinical endpoint looking at the risk of the most severe stage of
(HR = 1.44). When these cardiovascular diseases were analysed simul- CKD. These analyses show that prevalent and incident heart failure
taneously in a single model (e.g. adjusting for atrial fibrillation, coronary (HR = 4.5), coronary heart disease (HR = 3.1), atrial fibrillation
heart disease, and stroke for analysis of heart failure), heart failure re- (HR = 2.8), and stroke (HR = 2.0) all heavily impinge upon the risk of
mained the strongest risk factor (HR = 9.9) while, mainly due to insuf- KF-RRT. Understandably, the risk was highest in the first 3 months after
ficient power, atrial fibrillation and stroke were no longer significant these events, and gradually returned to baseline over 3 years. Thus, this
predictors of KF-RT. Overall, due to the shortcomings of surrogate study provides a much needed, large-scale confirmation of observations
endpoints of kidney failure and the insufficient power of the best obser- made by Ishigami et al. in the SCREAM12 and the ARIC study13 data-
vational studies, the prognostic implication of major cardiovascular bases. Notwithstanding the prevalence of kidney failure being treated
events for the terminal stage of CKD, KF-RRT remains insufficiently with dialysis at the population level is low (∼0.5–1.0 cases per thousand
characterized. The global prevalence of kidney failure was estimated people per year in economically advanced countries), it imposes very
to be 0.07% or ∼5.3 million people in 2017. Approximately a quarter high health costs, ∼2–3% of all health expenditures. This is a huge
of patients on haemodialysis die within a year of initiating therapy in cost competing with that of other more prevalent chronic diseases.
high-income countries, and this proportion is much higher in low- The link between cardiovascular diseases and kidney failure in the
and middle-income countries.14 The ‘dialysis market’ is in an expanding chronic diseases scenario (Graphical Abstract) is of particular import-
phase. In 2021 the cost of dialysis worldwide was US$109 billion, and it ance because cardiovascular diseases rank as the major health burden
Editorial 3

in the adult population worldwide. The findings by Patrick Mark15 sug- 4. Windt WAKM, Eijkelkamp WBA, Henning RH, Kluppel ACA, de Graeff PA, Hillege HL,
et al. Renal damage after myocardial infarction is prevented by renin–angiotensin–
gest that policies preventing heart failure, coronary artery disease, atrial
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fibrillation, and stroke, and early, timely treatment of the same diseases org/10.1681/ASN.2006030209
will protect not only the cardiovascular system but also the kidney. 5. Ljungman S, Laragh JH, Cody RJ. Role of the kidney in congestive heart failure.
Appropriate cardiovascular interventions targeting these diseases Relationship of cardiac index to kidney function. Drugs 1990;39:10–21. https://doi.

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may avert a not trivial proportion of CKD cases reaching the end-stage org/10.2165/00003495-199000394-00004
6. Mawhin MA, Bright RG, Fourre JD, Vloumidi EI, Tomlinson J, Sardini A, et al. Chronic
phase of this disease, thereby contributing to mitigating the human and kidney disease mediates cardiac dysfunction associated with increased resident cardiac
financial costs of kidney failure. Well beyond the critical cardio-renal macrophages. BMC Nephrol 2022;23:47. https://doi.org/10.1186/s12882-021-02593-7
connection, preventing the epidemic of chronic diseases, i.e. a set of 7. Chronic Kidney Disease Prognosis Consortium, Matsushita K, van der Velde M, Astor
highly interconnected diseases (Graphical Abstract), remains an absolute BC, Woodward M, Levey AS, et al. Association of estimated glomerular filtration rate
and albuminuria with all-cause and cardiovascular mortality in general population co-
public health priority in the years to come. horts: a collaborative meta-analysis. Lancet 2010;375:2073–2081. https://doi.org/10.
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8. Chen TH, Chu YC, Ou SM, Tarng DC. Associations of atrial fibrillation with renal func-
Data availability tion decline in patients with chronic kidney disease. Heart 2022;108:438–444. https://
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No new data were generated or analysed in support of this research. 9. Zoccali C, Bolignano D, Mallamaci F. Oxford textbook of clinical nephrology. In: Turner
NN, Lameire N, Goldsmith DJ, Winearls CG, Himmelfarb J, Remuzzi G (eds). Oxford
Textbook of Nephrology, 4th edn. Oxford University Press; 2015.
Conflict of interest 10. Zhao Q, Yan T, Chopp M, Venkat P, Chen J. Brain–kidney interaction: renal dysfunction
following ischemic stroke. J Cereb Blood Flow Metab 2020;40:246–262. https://doi.org/
C.Z. is a consultant to Fresenius Medical Care, Europe and received a 10.1177/0271678X19890931
fee for lecturing at Fresenius Medical Care Israel. F.M. has no conflict 11. Levey AS, Inker LA, Matsushita K, Greene T, Willis K, Lewis E, et al. GFR decline as an
end point for clinical trials in CKD: a scientific workshop sponsored by the national kid-
to declare.
ney foundation and the US food and drug administration. Am J Kidney Dis 2014;64:
821–835. https://doi.org/10.1053/j.ajkd.2014.07.030
12. Ishigami J, Trevisan M, Lund LH, Jernberg T, Coresh J, Matsushita K, et al. Acceleration of
Funding kidney function decline after incident hospitalization with cardiovascular disease: the
Stockholm CREAtinine measurements (SCREAM) project. Eur J Heart Fail 2020;22:
All authors declare no funding for this contribution. 1790–1799. https://doi.org/10.1002/ejhf.1968
13. Ishigami J, Cowan LT, Demmer RT, Grams ME, Lutsey PL, Carrero JJ, et al. Incident hos-
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