In 2002 the National Kidney Foundation Kidney Disease Outcomes Quality
Initiative (KDOQI) Work Group defined chronic kidney disease (CKD) as the
3-month presence of proteinuria or a persistently lowered glomerular filtration
rate (GFR) regardless of the underlying pathology. According to this definition,
almost 20 million adults in the United States have CKD, and yet another 20
million are considered at risk for developing CKD. Because of its growing
prevalence and its high socioeconomic burden, CKD has recently been termed the
'silent epidemic.' The course of CKD is marked by secondary complications such
as bone disease and anemia as well as a considerably increased risk for
cardiovascular disease and, in a minority of patients, the progression to
end-stage renal disease.

Age, background cardiovascular risk, and the etiology of kidney disease have all
been described as impacting the progression of the disease independent of
baseline CKD stage. A recent study by O'Hare et al. convincingly demonstrated
the flaws of a purely GFR-based approach to CKD patients by showing a tenfold
increase in the ratio of necessary to unnecessary vascular access surgery in
elderly patients.[1] A GFR-independent marker of disease progression would help
clinicians to tailor therapy and intervention and to base their decisions on the
individual patient's risk.

Dieplinger et al.[2] (this issue) describe the ability of pro-A-type natriuretic
peptide and pro-adrenomedullin to predict disease progression in patients with
nondiabetic kidney disease enrolled in the Mild to Moderate Kidney Disease
(MMKD) Study.

A-type natriuretic peptide (ANP) is a cardiac peptide with potent natriuretic,
vasodilator, and diuretic actions. ANP stems from the enzymatic cleavage of its
precursor proANP, which is significantly more stable than the active breakdown
product. The co-released, inactive N-terminal split product is subject to
further enzymatic fragmentation, leaving the midregional breakdown product
MR-proANP as a stable and readily measurable parameter of circulating ANP
levels. ANP is primarily secreted from the cardiac atria in response to volume
overload and myocyte stretch. Increased levels of ANP have been observed in
heart failure, left ventricular dysfunction, coronary artery disease, and renal
failure.

Adrenomedullin (ADM) is also a potent natriuretic and vasodilatory peptide. It
has a short half-life and is derived from the cleavage of a larger precursor
molecule, proADM. MR-proADM is stable at room temperature and can be measured by
a sandwich immunoassay. MR-proADM directly reflects circulating adrenomedullin
levels. Increased adrenomedullin levels have been observed in disorders
associated with hypervolemia, such as heart failure, myocardial infarction, and
ESRD under hemodialysis. Pathologically increased adrenomedullin levels were
recently shown to reflect the degree of underlying cardiac dysfunction.[3,4]
While adrenomedullin has been detected in multiple tissues, disease-induced
secretion appears to stem from biventricular cardiac dilation[5] and increased
vascular shear stress.[6]

During the 7-year follow-up period covered in the MMKD Study, the combined end
point of a doubling of serum creatinine or disease progression to ESRD requiring
renal replacement therapy was reached in 65 of 177 patients. In accordance with
previous studies, Dieplinger et al.[2] found patients reaching this end point to
be older and to display higher levels of proteinuria and lower GFR.
Additionally, the authors reported higher levels of MR-proANP and MR-proADM in
progressors. The predictive accuracy of these novel biomarkers was equal to the
predictive potential of baseline GFR values (AUCMR-proANP=0.810,
AUCMR-proADM=0.876, AUCGFR=0.838). Remarkably, MR-proANP and MR-proADM retained
high diagnostic accuracy even after the adjustment for the most common cofactors
for disease progression: age, sex, GFR, and proteinuria. These results suggest
that MR-proANP and MR-proADM, two reliable markers of cardiac dysfunction, could
help clinicians to estimate the pace of disease progression, even in patients
with equal GFR and proteinuria levels.

This study extends and corroborates similar findings from the same cohort for
NT-proBNP, a quantitative marker of cardiac stress that is released
predominantly by the cardiac ventricles. BNP and NT-proBNP are co-secreted and,
under non-stressed conditions, are found only in atrial granules. In response to
stress, however, BNP and NT-proBNP are synthesized, stored, and released mainly
from ventricular myocardium. The primary stimulus for BNP and NT-proBNP
formation seems to be end-diastolic wall stress.

One important limitation, which was appropriately acknowledged by the authors,
is the lack of detailed functional and structural cardiac assessment (for
example, echocardiography) and therefore the inability to elucidate whether
MR-proANP and MR-proADM were associated with CKD progression independently of
the presence of structural and/or functional cardiac disease or whether
clinically undetected cardiac disease at least to some extent triggered the
deterioration of renal function.

The interplay between the heart and the kidneys has received widespread
attention in recent years (Figure 1). Initially, the 'cardiorenal syndrome' has
generally been considered to be driven by a failing heart causing a secondary
deterioration of kidney function. In this setting, impaired kidney function has
convincingly been shown to be associated with a significantly reduced patient
survival. This simplistic and unidirectional view has recently been challenged
after accelerated cardiac atherosclerosis, left ventricular hypertrophy and
remodeling, and myocardial microangiopathy were observed in primary kidney
diseases.[7]

To accommodate these important kidney-heart interactions, a novel five-classed
definition of cardiorenal syndromes (CRS) has been proposed.[8] In this
classification, types 1 and 2 represent the acute and chronic forms of the
'classic' cardiorenal syndrome, in which decreased cardiac function induces a
progressive and potentially permanent decline in kidney function. Similarly,
types 3 and 4 represent the acute and chronic forms of the 'renocardiac'
syndrome, in which primary kidney disease induces acute (for example, heart
failure, arrhythmia) or chronic (for example, hypertrophy, coronary
atherosclerosis) cardiac disorders. An additional type 5 includes systemic
diseases such as sepsis, amyloidosis, and systemic lupus erythematosus that are
able to induce cardiac as well as renal dysfunction.

Hence, the ability of two markers of cardiac dysfunction to predict progression
of primary kidney disease, described by Dieplinger and his co-workers,[2]
highlights the prognostic importance of the chronic cardiorenal syndromes (CRS
types 2 and 4).

Unfortunately, this obvious pathophysiological link between CKD and cardiac
dysfunction is confronted by a significant underprescription of cardiovascular
disease-modifying pharmacotherapy in CKD patients. A recent, alarming study
investigating patients after acute myocardial infarction found less than 50% of
all CKD patients to be treated with a combination of aspirin, beta-blockers,
angiotensin-converting enzyme (ACE) inhibitors, and statins.[9] Only the
minority of CKD patients receiving standard combination drug therapy experienced
30-day survival similar to that of non-CKD patients. This lack of
guideline-conforming therapy is generally caused by concerns over increasing
creatinine levels and potential nephrotoxicity. However, a short-term, ACE
inhibitor-associated increase in serum creatinine was found to reflect
successful nephroprotection in patients with renal insufficiency by a large
metaanalysis.[10]

While research activities in the cardiorenal syndromes are only beginning to
grow and consensus definitions are only being discussed, clinicians may
presently not be able to stop the vicious cycle of declining renal and cardiac
function but can nevertheless significantly slow down its progression. Treating
the shared risk factors by adequately lowering blood pressure and sufficiently
blocking the renin-angiotensin system as well as by controlling diabetes
mellitus, treating dyslipidemia, and advocating smoking cessation remains of
pivotal importance. We as clinicians need to consider and attempt to use these
powerful tools in all our CRS patients.