commentary

the CaSR in the proximal tubule is a

molecular link remains to be clarified. see clinical investigation on page 353

DISCLOSURE
Acute myocardial infarction in
The author declared no competing interests.
patients with chronic kidney
ACKNOWLEDGMENTS
Work in the laboratory of the author is
disease: how are the most
supported by the Swiss National Science
Foundation (31003A_138143 and NCCR
Kidney.CH).
vulnerable patients doing?
Gautam R. Shroff1 and Charles A. Herzog1,2
REFERENCES
1. Riccardi D, Brown EM. Physiology and Patients with advanced chronic kidney disease sustain extremely
pathophysiology of the calcium-sensing
receptor in the kidney. Am J Physiol Renal high mortality rates following acute myocardial infarction. Nauta et al.
Physiol 2010; 298: F485–F499.
2. Brown EM, Gamba G, Riccardi D et al.
evaluated temporal trends in 12,087 patients with acute myocardial
Cloning and characterization of an infarction from a single institution over 24 years and report a reduction
extracellular Ca(2 þ )-sensing receptor from
bovine parathyroid. Nature 1993; 366: in 30-day mortality in the most recent decade for all patients, including
575–580. patients with chronic kidney disease. This trend is optimistic, but
3. Brown EM. Clinical lessons from the calcium-
sensing receptor. Nat Clin Pract Endocrinol understanding contributory factors would be critical in future studies
Metab 2007; 3: 122–133.
4. Loupy A, Ramakrishnan SK, Wootla B et al.
to further improve survival.
PTH-independent regulation of blood Kidney International (2013) 84, 230–233. doi:10.1038/ki.2013.151
calcium concentration by the calcium-
sensing receptor. J Clin Invest 2012; 122:
3355–3367.
5. Toka HR, Al-Romaih K, Koshy JM et al. Recent decades have seen progressive mortality from AMI between 2002 and
Deficiency of the calcium-sensing receptor in improvements in the management of 2010, and inferred that more than half
the kidney causes parathyroid hormone-
independent hypocalciuria. J Am Soc Nephrol
acute myocardial infarction (AMI) the decline was attributable to reduced
2012; 23: 1879–1890. worldwide. Dating back to the intro- event rates and slightly less than half
6. Sands JM, Naruse M, Baum M et al. Apical duction of thrombolytic therapy in the to improved 30-day survival.
extracellular calcium/polyvalent cation-
sensing receptor regulates vasopressin- early 1990s, consistent and incontro- However, we must judge the
elicited water permeability in rat kidney inner vertible advances in management para- progress made on the basis of the
medullary collecting duct. J Clin Invest 1997; digms for AMI have directly impacted extent to which the most vulnerable
99: 1399–1405.
7. Renkema KY, Velic A, Dijkman HB et al. patient survival. These strategies in- patient subgroups have benefited from
The calcium-sensing receptor promotes clude a focus on early invasive inter- these advances. Patients with renal
urinary acidification to prevent nephro-
lithiasis. J Am Soc Nephrol 2009; 20:
vention, evolution of pharmacological dysfunction in the context of AMI
1705–1713. therapies (antiplatelet agents, statins, constitute one of the highest-risk sub-
8. Ba J, Brown D, Friedman PA. Calcium-sensing neurohormonal antagonists to address sets, owing to a substantially higher
receptor regulation of PTH-inhibitable
proximal tubule phosphate transport. left ventricular remodeling), and, most burden of cardiovascular disease and
Am J Physiol Renal Physiol 2003; 285: recently, establishment of a systems higher mortality and complication
F1233–F1243. approach to regional AMI care. In a rates. Using a population cohort from
9. Riccardi D, Traebert M, Ward DT et al. Dietary
phosphate and parathyroid hormone alter study evaluating the National Health Alberta, Canada, Tonelli et al. demon-
the expression of the calcium-sensing Service database in England, Smolina strated significantly higher incident
receptor (CaR) and the Na þ -dependent Pi
transporter (NaPi-2) in the rat proximal
et al.1 described an approximately AMI rates with chronic kidney disease
tubule. Pflugers Arch 2000; 441: 379–387. 50% decline in age-adjusted all-cause (CKD; estimated glomerular filtration
10. Capasso G, Geibel PJ, Damiano S et al. The rateo45 ml/min per 1.73 m2 and severe
calcium sensing receptor modulates fluid
reabsorption and acid secretion in the 1
proteinuria) than with diabetes (12.4
proximal tubule. Kidney Int 2013; 84: 277–284.
Division of Cardiology, Department of Medicine, versus 6.6 per 1000 person-years) and
11. Pan W, Borovac J, Spicer Z et al. The epithelial Hennepin County Medical Center and University
of Minnesota, Minneapolis, Minnesota, USA and
recommended that CKD be considered
sodium/proton exchanger, NHE3, is
necessary for renal and intestinal calcium 2
Chronic Disease Research Group, Minneapolis a coronary risk equivalent.2 Data from
(re)absorption. Am J Physiol Renal Physiol Medical Research Foundation, Minneapolis, the US Renal Data System (USRDS)
2012; 302: F943–F956. Minnesota, USA
12. Nijenhuis T, Vallon V, van der Kemp AW et al.
establish a graded increase in AMI
Correspondence: Gautam R. Shroff, Division of rates and probability of mortality
Enhanced passive Ca2 þ reabsorption and
reduced Mg2 þ channel abundance explains
Cardiology, Department of Medicine, Hennepin
County Medical Center, 701 Park Avenue,
with advancing CKD stages (Figure 1).
thiazide-induced hypocalciuria and
hypomagnesemia. J Clin Invest 2005; 115: Minneapolis, Minnesota 55415, USA. Among patients with AMI and heart
1651–1658. E-mail: shrof010@umn.edu failure/left ventricular dysfunction,

230 Kidney International (2013) 84

 commentary

40
2007
0.8
Outcomes Network–Get with the
Fatal No CKD Guidelines (ACTION-GWTG) registry,
Rate per 1000 patient-years
Nonfatal All CKD evaluated 13,872 patients presenting

Probability of death
30 0.6
with non-ST-segment elevation myo-
cardial infarction (non-STEMI) who
20 0.4 received no revascularization proce-
Stages 1–2 dures despite an initial angiogram. In
10 0.2 Stage 3 this study, about 44% of patients had
Stages 4–5 CKD; in-hospital mortality and bleed-
0 0.0
ing rates were highest in patients with
0 6 12 18 24 30 36 advanced CKD, who were least likely
KD

St 2

5
1–

4–
St CK

St age
C

Months after cardiac event to receive guideline-recommended

es

es
o

l
Al
N

ag

ag

therapy (including revascularization).

Figure 1 | Data from the US Renal Data System demonstrating a graded relationship Thus, another paradoxical theme con-
between advancing stages of CKD and rates of fatal and nonfatal myocardial infarction, sistently emerges from the existing
2007, and probability of death following myocardial infarction, 2007–2008. (Data from
the US Renal Data System, 2012 Annual Data Report: Atlas of Chronic Kidney Disease and
literature. Despite the significantly
End-Stage Renal Disease in the United States, National Institute of Diabetes and Digestive and higher risk of mortality and adverse
Kidney Diseases, National Institutes of Health, Bethesda, MD, USA, 2012, vol. 1, ch. 4, p. 79.) cardiovascular outcomes with AMI,
patients with advanced CKD are much
less likely to receive evidence-based
minor declines in estimated glomerular are well established and effective in the therapies, including invasive evaluation
filtration rate are associated with general population simply be extrapo- and revascularization procedures.4,5,12
increased probability of mortality lated to patients with CKD? Patients Many possible explanations can be
and adverse cardiovascular outcomes.3 with CKD differ pathobiologically and hypothesized. Clinicians may find the
The Acute Coronary Treatment and clinically from patients with normal absence of randomized evidence a
Intervention Outcomes Network renal function, making the notion of deterrent to using conventionally
(ACTION)4 and Swedish Web-System routine extrapolation problematic. accepted evidence-based therapies, or
for Enhancement and Development of Patients with an estimated glomerular experience a sense of ‘therapeutic
Evidence-Based Care in Heart Disease filtration rate less than 45 ml/min per nihilism’ toward this population due
Evaluated According to Recommended 1.73 m2 are significantly more likely to to poor outcomes. Alternatively, the
Therapies (SWEDEHEART) registries5 experience an index presentation with relative underuse of therapies could
reiterate the severalfold higher odds AMI than with stable angina.8 However, be secondary to fear of complications,
of in-hospital mortality with AMI clinicians’ ability to recognize AMI particularly bleeding and contrast
in patients with advanced CKD. in patients with advanced CKD may nephropathy.
Among patients receiving maintenance be compromised because of atypical Against this backdrop, Nauta and
dialysis, survival rates with AMI are presentations (reduced prevalence coauthors10 (this issue) evaluated
dismal; Iseki and Fukiyama reported of chest pain, diagnostic electrocardio- temporal trends in mortality in 12,087
a fourfold higher incidence of AMI and graphic abnormalities) and advanced patients with AMI and varying degrees
a more than twofold higher risk of hemodynamic class at presentation.9 of renal dysfunction over nearly
30-day mortality following AMI (49.2 Interestingly, the burden of some ‘con- two-and-a-half decades. Notably, 2347
versus 22.9%) among maintenance ventional’ cardiovascular risk factors patients (16%) had to be excluded at
hemodialysis patients in Okinawa, Japan, (for instance, family history, smoking, the outset owing to lack of at least one
compared with the general population.6 dyslipidemia) is substantially lower in baseline creatinine value; some of these
Using USRDS data, Herzog et al. had CKD patients than in the general patients may have died shortly after
previously reported in-hospital mortality population.9,10 Moreover, the location admission (before laboratory data were
of 26% and 1-year mortality of 59% of the coronary culprit lesion in AMI is available), and therefore this may
following AMI.7 more proximal in patients with CKD, represent the highest-risk subgroup in
It is therefore paradoxical, albeit well possibly leading to higher event rates or the cohort. Also, all patients were
recognized, that despite their status as threatening a larger myocardial volume.11 admitted to the coronary care unit of
the highest-risk subset of patients with CKD also independently predicts major the Erasmus University Medical
AMI, patients with advanced CKD (and bleeding following AMI, making the Center, and the cohort comprised a
on dialysis) have been routinely ex- decision to use aggressive management high percentage of patients with
cluded from randomized trials evaluat- with antithrombotic therapies signifi- STEMI, adding several dimensions to
ing strategies that impact survival with cantly thornier for clinicians. the biases involved (referral population
AMI. In the absence of specific evi- Hanna et al.,12 using the Acute in an academic hospital, patients dying
dence, can therapeutic advances that Coronary Treatment and Intervention before unit admission excluded).

Kidney International (2013) 84 231

commentary
Data were abstracted by trained
personnel, but several key clinical
variables (hemodynamic parameters,
ejection fraction, proteinuria) were not
available. This study offers reliable
estimates of glomerular filtration rate
using contemporaneous methods, but
because of smaller numbers of stage
4–5 CKD patients (4% of the cohort),
discrete information regarding dialysis
patients was unfortunately not available.
Despite these limitations (duly
acknowledged by the authors), these
observational data tell an informative
and optimistic story of temporal
reduction in 30-day mortality among
patients with various degrees of renal
dysfunction (71% had stage 2–5 CKD)
in the most recent decade. Are these
results surprising to clinicians? Given
the preceding discussion regarding the
high-risk nature of the intersection of
CKD and AMI, lack of randomized
evidence, and higher complication
rates, a temporal decrease in mortality
associated with AMI among patients in
this study is reassuring. Importantly,
although these observational data
are extremely interesting, they do not
provide a proximate explanation for the
reasons underlying the reduced mor-
tality. The authors demonstrate that use
of evidence-based therapies (including
revascularization) increased during the
study period, although these therapies
were underused with more advanced
CKD. Although no causality can be
determined from these observational
data, one could conjecture (particularly
since the greatest impact was on short-
term mortality rates) that these find-
ings reflect a gradual dissemination
of evidence-based therapies derived
from the general population to CKD
patients.
Are these data generalizable to all
patients with advanced CKD in
the contemporary era of percutaneous
coronary intervention? The population
studied by Nauta et al.10 is highly
selected, as the patients were from a
single academic facility with established
expertise in the management of AMI.
Therefore, despite the optimistic signal
from this study, these results need
to be duplicated and verified in a
232
more diverse patient population with
differing demographics receiving care
from clinicians with a wider range of
expertise. Interestingly, a similar trend
in mortality reduction has been
described among dialysis patients
with AMI. Using data from the
USRDS, we have preliminarily
reported13 a significant reduction in
30-day mortality (36 versus 24%) and
1-year mortality (64 versus 54%)
among dialysis patients with AMI
between 1993 and 2008. On further
characterization of these data, it was
evident that the reduction in mortality
was significant only among patients
with STEMI (30-day mortality
43 versus 30%), not in non-STEMI
patients (18 versus 20%). In light of
these observations, it is conceivable that
the reduction in mortality demon-
strated by Nauta et al.10 occurred
predominantly because of reduced
mortality in the unusually high
percentage of STEMI patients with
possibly less advanced degrees of CKD
(46% stage 2, 21% stage 3) in the
cohort. This requires verification in
future studies; in fact, the authors are
encouraged to evaluate in a future
analysis whether the mortality trends
were similar in STEMI and non-STEMI
subgroups.
Finally, this study serves as a sobering
and humbling reminder that despite the
optimistic trend, mortality rates of pa-
tients with severe CKD remain strikingly
high; the median survival of patients with
stage 4–5 CKD was merely 22 months
following AMI. As a medical community,
we cannot continue to simply rely on
observational data to address these
high mortality rates. Although some
improvements may have occurred
serendipitously, we are unlikely to make
continued progress or to deepen our
understanding of the disease pathophy-
siology if we continue to exclude these
high-risk patients, the most vulnerable
subset of patients with AMI, from
our randomized controlled trials. The
high cardiovascular event rates would
serve to reduce the sample size necessary
to demonstrate beneficial effects of
specific therapies among patients with
CKD.
DISCLOSURE
The authors declared no competing interests.
ACKNOWLEDGMENTS
The authors thank Chronic Disease Research
Group colleagues Delaney Berrini, for
manuscript preparation, and Nan Booth,
for manuscript editing.
REFERENCES
1. Smolina K, Wright FL, Rayner M et al.
Determinants of the decline in mortality
from acute myocardial infarction in
England between 2002 and 2010: linked
national database study. BMJ 2012; 344:
d8059.
2. Tonelli M, Muntner P, Lloyd A et al. Risk of
coronary events in people with chronic
kidney disease compared with those with
diabetes: a population-level cohort study.
Lancet 2012; 380: 807–814.
3. Anavekar NS, McMurray JJ, Velazquez EJ et al.
Relation between renal dysfunction and
cardiovascular outcomes after myocardial
infarction. N Engl J Med 2004; 351:
1285–1295.
4. Fox CS, Muntner P, Chen AY et al. Use of
evidence-based therapies in short-term
outcomes of ST-segment elevation
myocardial infarction and non-ST-segment
elevation myocardial infarction in patients
with chronic kidney disease: a report from
the National Cardiovascular Data Acute
Coronary Treatment and Intervention
Outcomes Network registry. Circulation 2010;
121: 357–365.
5. Szummer K, Lundman P, Jacobson SH et al.
Influence of renal function on the effects of
early revascularization in non-ST-elevation
myocardial infarction: data from the Swedish
Web-System for Enhancement and
Development of Evidence-Based Care in
Heart Disease Evaluated According to
Recommended Therapies (SWEDEHEART).
Circulation 2009; 120: 851–858.
6. Iseki K, Fukiyama K. Long-term prognosis and
incidence of acute myocardial infarction in
patients on chronic hemodialysis. The
Okinawa Dialysis Study Group. Am J Kidney
Dis 2000; 36: 820–825.
7. Herzog CA, Ma JZ, Collins AJ. Poor
long-term survival after acute myocardial
infarction among patients on long-term
dialysis. N Engl J Med 1998; 339:
799–805.
8. Go AS, Bansal N, Chandra M et al. Chronic
kidney disease and risk for presenting with
acute myocardial infarction versus stable
exertional angina in adults with coronary
heart disease. J Am Coll Cardiol 2011; 58:
1600–1607.
9. Shroff GR, Frederick PD, Herzog CA. Renal
failure and acute myocardial infarction:
clinical characteristics in patients with
advanced chronic kidney disease, on dialysis,
and without chronic kidney disease. A
collaborative project of the United States
Renal Data System/National Institutes of
Health and the National Registry of
Myocardial Infarction. Am Heart J 2012;
163: 399–406.
10. Nauta SJ, van Domburg RT, Nuis R-J et al.
Decline in 20-year mortality after myocardial
infarction in patients with chronic kidney
Kidney International (2013) 84
 commentary

disease: evolution from the prethrombolysis elevation myocardial infarction found have we been evaluating specific
to the percutaneous coronary intervention to have significant coronary artery disease
era. Kidney Int 2013; 84: 353–358. on coronary angiography and managed recipient risk profiles for PVAN occur-
11. Charytan DM, Kuntz RE, Garshick M et al. medically: stratification according to rence and unfortunate premature renal
Location of acute coronary artery throm- renal function. Am Heart J 2012; 164:
boses in patients with and without chronic 52–57.
allograft loss.
kidney disease. Kidney Int 2009; 75: 13. Shroff GR, Li S, Herzog CA. Survival of US Allografts injured by PVAN have
80–87. dialysis patients after acute myocardial diminished survival rates in part due to
12. Hanna EB, Chen AY, Roe MT et al. infarction: is it finally getting better in the
Characteristics and in-hospital outcomes of modern treatment era? Circulation 2012; the lack of a clinically proven effective
patients presenting with non-ST-segment 126(Suppl): A11138. antiviral treatment to control or block
BKV replication. The current standard of
care of patients identified as having BKV
see clinical investigation on page 359 replication or PVAN is immunosuppres-
sant reduction, which can reduce renal
Natural killer cell response to allograft loss when BKV replication or
PVAN is detected early before significant
BK virus infection in polyoma allograft dysfunction. BKV screening
programs after renal transplantation
virus–associated nephropathy are effective but costly and are not
universally available to evaluate all
of renal transplant recipients patients at risk for BKV replication. A
strategy to stratify only renal allograft
Philip D. Acott1,2 recipients at risk of BKV replication
to longitudinal monitoring would po-
The mechanisms of injury and advantage secured by opportunistic tentially simplify screening algorithms2
infection with polyoma virus in renal transplant patients are not with associated cost savings by focusing
completely known. Patient virus-specific T cells play a large role in resources of enhanced screening
surveillance programs on the at-risk
elimination of reactivated polyoma virus. Natural killer (NK) cells
cohort. Despite consensus that the
are early responders in antiviral response. Inflammatory NK-cell initial treatment for BK viremia and/or
antiviral responses involve activation receptors such as killer-cell PVAN should be a judicious decrease
immunoglobulin-like receptors (KIRs) interacting with host-cell major of immunosuppression, there is a lack of
histocompatibility complex class I molecules, altering cell sensitivity consensus as to which immunosup-
to lysis by NK cells. pressant agents should be altered
Kidney International (2013) 84, 233–235. doi:10.1038/ki.2013.148
first and by how much. In addition,
few studies have focused on adjunctive
therapies, which are commonly used
in PVAN patients when coincident
Gardner et al. reported the first post- impact on renal allograft function. BK rejection occurs. Despite all of these
renal-transplantation polyoma virus virus (BKV) and the related JC virus are issues, renal allograft survival with
infection in a patient with the initials now the most important primary or PVAN is improving in most centers,
BK in 1971.1 Despite four decades reactivating viruses targeting renal probably owing to more awareness of
of improved renal transplantation tissue in both the renal transplant and PVAN and early-intervention strategies.
outcomes, we are still perplexed the solid-organ transplant population. A review of the literature evaluating
by the mechanisms of injury and Polyoma virus–associated nephropathy the relationship between immuno-
advantage secured by opportunistic (PVAN) is an avoidable negative suppression and BKV reactivation3 indi-
infection with polyoma virus in the outcome for both of these transplant cated that specific immunosuppressant
renal transplant population. Since 1995 populations. Prevention strategies agents potentiate BKV reactivation,
there has been a major increase in the and efforts for early recognition are including thymoglobulin, tacrolimus-
incidence of polyoma virus and its the key clinical elements required to based regimens, and tacrolimus with
lessen injury to renal allografts and mycophenolate mofetil. It is unclear
1
Pediatrics, Pharmacology, Medicine, Surgery, require an understanding of which whether these agents potentiate risk
Dalhousie University, Halifax, Nova Scotia, patient groups are most at risk. PVAN solely through their specific T-cell
Canada and 2Nephrology, IWK Health Centre, causes renal allograft dysfunction in effects or through indirect effects on
Halifax, Nova Scotia, Canada 60–90% of patients affected, with even- renal tissue or other antiviral pathways.
Correspondence: Philip D. Acott, IWK Health
Centre, 5850 University Avenue, Halifax, Nova
tual early allograft loss in about 50% of Patient virus-specific T cells play a
Scotia, Canada B3K 6R8. cases. Despite many studies outlining large role in elimination of reactivated
E-mail: Philip.acott@iwk.nshealth.ca risk factors for PVAN, only recently BKV. However, in the absence of

Kidney International (2013) 84 233