commentary

3. Schlieper G, Brandenburg V, Djuric Z et al. Risk 5. Cheung C, Bernardo AS, Trotter MW et al. clinical significance of basic structural
factors for cardiovascular calcifications in non- Generation of human vascular smooth muscle changes.
diabetic Caucasian haemodialysis patients. subtypes provides insight into embryological
Kidney Blood Press Res 2009; 32: 161–168. origin-dependent disease susceptibility. Nat The simplest structural parameter is
4. Leroux-Berger M, Queguiner I, Maciel TT et al. Biotechnol 2012; 30: 165–173. kidney size, a decrease in which is frequent
Pathologic calcification of adult vascular 6. Bostrom KI, Rajamannan NM, Towler DA.
smooth muscle cells differs on their crest or The regulation of valvular and vascular
in advanced CKD and is often used to
mesodermal embryonic origin. J Bone Miner sclerosis by osteogenic morphogens. Circ Res confirm this diagnosis. It is reasonable to
Res 2011; 26: 1543–1553. 2011; 109: 564–577. assume that this loss begins at earlier
stages of CKD, but, amazingly, there has
been little attention to this as a clinical or
see clinical investigation on page 677 research tool. Even though it is well
known that kidney size varies with body
Structure, not just function size, there are no published nomograms
based on data from subjects without renal
W. Charles O’Neill1 disease that can be used to analyze kidney
size in adults. Therefore, most renal
Although kidney size can be important in the evaluation of renal sonograms are interpreted without correc-
disease, it has not been carefully studied and true volume is rarely tion for or even consideration of body
measured, and good normative data are lacking. Wang et al. measured size, clearly limiting the ability to recog-
nize CKD at earlier stages. Other potential
both cortical and medullary volumes in potential transplant donors and
determinants of kidney size, such as sex
correlate these with physiologic, morphometric, and metabolic and age, are also not considered. Although
parameters. The results reveal interesting and potentially important these corrections would enhance the
correlations and differential responses between the two compartments, ability of ultrasound to recognize kidney
providing a framework for future investigation. disease at an earlier stage, this is limited by
Kidney International (2014) 85, 503–505. doi:10.1038/ki.2013.426 the imprecision of ultrasound.
Sonographic measurement of kidney
volume entails measuring three orthogo-
Nephrologists usually take a dysfunc- the poor correlation between estimated nal dimensions and modeling the kidney
tional approach to kidney disease. Not GFR and true GFR when serum creatinine as an ellipsoid. However, there are errors
that there is anything wrong with us, is in the normal range.1 Therefore, if we are in these measurements, particularly in the
but our detection of kidney disease and to improve our diagnostic and prog- two transverse dimensions, that become
stratification of its severity are based nostic approach to kidney disease, we very large when multiplied in the for-
almost entirely on altered function must move beyond measurements of mula. Furthermore, the kidney rarely
rather than structure. On top of that, function and focus on structural changes approximates an ellipsoid and varies
we take a glomerulocentric view of as well. The study by Wang et al.2 (this considerably in shape. Thus renal length
kidney dysfunction, focusing only on issue) is an important step in this direction. is the only useful sonographic indication
albuminuria and reduced glomerular Recent studies have demonstrated of kidney size, but its correlation with
filtration rate (GFR) as if the kidney the potential utility of simple structural actual volume is poor.10 Accurate
consists exclusively of cortex composed changes, recognizable by standard non- measurements of kidney volume require
entirely of glomeruli. Kidney disease is invasive imaging, in identifying and either computed tomography or magnetic
presumed absent when glomerular managing CKD. A good example is resonance imaging with summation of
function is normal, and thus many autosomal dominant polycystic kidney cross-sectional areas from multiple
cases of early disease are missed, while disease, in which decreased GFR occurs sequential images. Their relative utility is
chronic kidney disease (CKD) or acute too late in the disease to be a useful dictated by availability, cost, and radiation
kidney injury is diagnosed when GFR is parameter for prognosis or evaluating exposure.
decreased, even though the dysfunction therapies. However, renal enlargement The kidney is also composed of non-
may be entirely hemodynamic and the occurs much earlier and can accurately parenchymal tissues (sinus fat, calyces,
kidneys structurally normal. Additional predict disease progression.3 Sporadic blood vessels, nerves, and lymphatics),
problems with this approach are the cysts, long thought to be of little clini- and recent studies have used computed
impracticality of measuring GFR and cal significance, are associated with tomography to exclude them in order to
reduced kidney size and altered func- measure true parenchymal volume. A
1
Renal Division, Emory University School of tion4–6 and are probably an early indi- prior study of 224 potential kidney
Medicine, Atlanta, Georgia, USA cator of underlying damage.7 Renal transplant donors11 found a strong
Correspondence: W. Charles O’Neill, Emory
University, Renal Division, WMB 338, 1639 Pierce
enlargement occurs early in diabetes correlation between renal parenchymal
Drive, Atlanta, Georgia 30322, USA. and is a risk factor for nephropathy.8,9 volume and body surface area (r ¼ 0.68),
E-mail: woneill@emory.edu These examples demonstrate the a larger volume in males independent of

Kidney International (2014) 85 503

commentary
Total
Volume
Medulla
Cortex
Age 20 40
Figure 1 | Effect of age on kidney size. Cortical volume appears to decrease throughout
adulthood, but whether this is due to nephron loss or decreased nephron size is unclear.
Because of an increase in medullary volume, which could be compensatory, total parenchymal
volume remains unchanged. When the increase in medullary volume ceases after age 60, total
volume decreases.
body size, and no decrease with age
(though there were few subjects older
than 60 years). Wang et al. used the same
approach in 1344 subjects and, remark-
ably, found the identical correlation
between parenchymal volume and body
surface area, again with greater volume in
males and little effect of age up to 60.2
However, they went a step further and
also examined the cortical and medullary
compartments, which can be distin-
guished on different phases of a contrast-
enhanced scan. Importantly, they found
that cortical volume decreases throughout
adulthood and is masked by an increase in
medullary volume (Figure 1). This rela-
tionship differed slightly in females, and,
interestingly, certain metabolic parameters
also correlated differently with cortical
and medullary volume, the meaning of
which remains to be determined.
Of the many questions about kidney
size that remain to be answered, two
important ones are the identity of other
determinants of size and the relationship
with function. Body size, age, and sex
account for only about half the variability
in renal parenchymal volume,11 and even
after correction for these variables, kidney
volume varies as much as twofold bet-
ween subjects. Is this due to differences in
nephron number, which is fixed in the
neonatal period and can vary as much as
eightfold,12,13 or is it due to differe-
504
60
nces in nephron size? The latter could be
the result of diet or of other metabolic
parameters, as explored by Wang et al.2
Although glycemia correlated with paren-
chymal volume or cortical volume, this is
probably explained by overweight, as the
correlation was lost when volume was
corrected for body size. A direct effect of
obesity on parenchymal volume was shown
in patients before and after weight loss in
the previously cited study.11 GFR correlates
strongly with parenchymal volume11— as
Wang et al. confirm2—and parenchymal
volume accounts entirely for the effects of
body surface area, age, sex, and ethnicity on
GFR.11 Although Wang et al. showed that
cortical volume also correlates strongly
with GFR, this could not fully account
for the age-related decline in GFR. The fact
that GFR varies almost twofold in subjects
with similar volumes indicates additional
variability in single-nephron GFR or
tubular mass per nephron.
Whether kidney size drives GFR or vice
versa and whether size is a risk factor for
CKD are additional important questions
that cannot be answered by cross-sectional
studies. The positive correlation between
cortical volume and albuminuria found by
Wang et al.2 is intriguing and suggests that
volume measurements may have pro-
gnostic value. Interestingly, this was not
explained by GFR in a multivariate model,
suggesting that it may not be simply due to
hyperfiltration. Other cardiovascular risk
factors such as smoking, uric acid, and
high-density lipoprotein cholesterol also
correlated with cortical or medullary
volume, again supporting the potential of
parenchymal volume as a risk factor.
Future longitudinal studies will be needed
to explore these tantalizing findings.
Even the best of studies have limita-
tions that always need to be considered.
Although the study population was ap-
parently normal and healthy, there is a
potential selection bias that could have
influenced this. Specifically, it is reasonable
to assume that a large proportion of the
subjects were family members of patients
with advanced CKD and could have
shared genetic or familial traits that
predispose to CKD. Also, the differentia-
tion between cortex and medulla is a
functional rather than an anatomic dis-
tinction based on the delivery of the
contrast agent. The timing of the cortical
phase (and thus calculation of cortical and
medullary volumes) can vary between
individuals and is influenced by hemody-
namics, contrast dose, and rate of injec-
tion. Repeat studies by Wang et al. on
some of the subjects suggest that this
variability is not large.
While the study of Wang et al.2 does
not yield specific insights into CKD, it
raises important questions, demon-
strates the methodology to answer
them, and provides important referen-
ce data. It is clear that there is a
potentially very informative yet largely
unexplored role of simple structural
parameters in the evaluation of kidney
disease and that our approach to kidney
disease needs to become less
dysfunctional and more dysmorphic.
Unfortunately, few nephrologists have
much knowledge or understanding of
renal imaging, even fewer actually image
kidneys, and just a handful have an
academic focus in this area. Whereas the
anatomy of the nephron is well under-
stood by nephrologists, most are lost
when zooming out to the whole kidney.
Nephrologists will need to take a greater
interest in renal imaging and pay more
attention to structure, not just function.
DISCLOSURE
The author declared no competing interests.
Kidney International (2014) 85
 commentary

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4. Al-Said JM, O’Neill WC. Reduced kidney size 11. Johnson S, Rishi R, Andone A et al. confirms a high burden of white matter
in patients with simple renal cysts. Kidney Int Determinants and functional significance disease, atrophy, and cerebral infarcts,
2003; 64: 1059–1064. of renal parenchymal volume in adults.
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even in those without a known history
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computed tomography of potential kidney A stereologic study of glomerular number (1) Neurocognitive manifestations of
donors. Am J Kidney Dis 2012; 59: 611–618. and volume: preliminary findings in a
7. Grantham JJ. Solitary renal cysts: worth a multiracial study of kidneys at autopsy. cerebrovascular disease predomi-
second look? Am J Kidney Dis 2012; 59: 593–594. Kidney Int 2003; 63: 31–37. nantly affect executive function
domains rather than memory, and
most prior studies of individuals
see clinical investigation on page 693 with CKD reveal that executive
function is more severely affected
Cognitive impairment in chronic than other cognitive domains.3,4,7,8
(2) Systemic cardiovascular disease
kidney disease: keep vascular (CVD) and CVD risk factors are
associated with significantly worse
disease in mind executive function.7
(3) In earlier stages of CKD, higher
David A. Drew1 and Daniel E. Weiner1 levels of albuminuria, probably re-
presenting systemic vascular burden,
Cognitive impairment is a major cause of morbidity in people with are associated with both worse ex-
chronic kidney disease (CKD) and is associated with worse survival. Prior ecutive functioning and brain mag-
netic resonance image findings.5,9,10
data suggest a relationship between vascular disease and cognitive
(4) More intensive dialysis with more
impairment in individuals with CKD. Clinicians should be aware of the effective clearance of uremic so-
high rates of cognitive impairment that occur in all stages of CKD, lutes does not improve cognitive
which, although sometimes subtle, may impact comprehension and function.11
decision making and may herald future, more debilitating impairment.
Kidney International (2014) 85, 505–507. doi:10.1038/ki.2013.437 In addition to a high burden of
traditional CVD risk factors among
individuals with CKD, nontraditional risk
Cognitive impairment is a major cause of prevalent and more severe at lower levels factors such as inflammation may be
morbidity in chronic kidney disease of kidney function.2 For patients with more prominent in individuals with CKD
(CKD). Individuals with cognitive impair- kidney failure treated with dialysis, this and may also predispose to cardiovascular
ment often have lower quality of life, have translates to a prevalence of cognitive and cerebrovascular disease (Figure 1).
more difficulty adhering to medications, impairment anywhere from 30 to 70%.3,4 Few data exist on how inflammation in
and have worse survival.1 Importantly, Reflecting the complex medical is- individuals with CKD may contribute to
cognitive deficits become both more sues present in people with CKD, the abnormal brain function.
cause of cognitive impairment is prob- Attempting to address these questions,
1
Division of Nephrology, Department of Medicine, ably multifactorial in this population. Seidel et al.12 (this issue) performed a
Tufts Medical Center, Boston, Massachusetts, USA As in the general population, aging cross-sectional study evaluating cognitive
Correspondence: Daniel E. Weiner, Tufts Medical
Center, 800 Washington Street, Box #391, Boston,
patients with kidney disease can be at performance in 119 patients with CKD
Massachusetts 02111, USA. risk for developing Alzheimer’s disease, stages 3–5D as well as 54 control subjects,
E-mail: dweiner@tuftsmedicalcenter.org which initially affects memory most all of whom had an estimated glomerular

Kidney International (2014) 85 505