open access: Nature Reviews: Key Advances in Medicine

with respect to care-plan modification.
Confirmation that this simple test helps
to appropriately reclassify these patients
is important. Further studies will facilitate
our understanding.
Variability in outcomes between ethnic
groups and within CKD populations with
similar diseases, has been another source
of confusion over the past decades. Two
important breakthroughs were made in
2011 with respect to genetic determinants
of kidney disease. Firstly, the importance
of the apolipoprotein L1 (APOL1) gene in
predicting any form of progressive CKD in
African Americans, 2 will have a profound
impact on clinical care (by suggesting alternative
treatment), familial donation strategies
and our understanding of progressive
disease in this vulnerable population.
Secondly, in another study, the finding that
soluble urokinase-type plasminogen activator
receptor (suPAR) is an important propagator
of focal segmental glomerulosclerosis
(FSGS), given its ability to activate podocyte
β2 integrin, provides new insights into this
condition. 3 In an elegant set of experiments,
Wei et al. demonstrated the importance of
elevated levels of suPAR in patients with
FSGS, and found that lowering of suPAR
levels with plasmapheresis led to remission
of disease. 3 Using a series of mouse models,
Wei and collaborators clearly identified a
relationship between suPAR and podocyte
damage. Although the reason for the elevation
in suPAR levels remains to be determined,
the fact that not all patients with
FSGS have high levels of this protein further
confirms that FSGS is a response to injury
rather than a specific disease. Improving
diagnostics and identifying new therapies
based on a better understanding of the
pathobiology is becoming possible with
discoveries such as those described above.
‘‘ Overall, 2011 was an
astounding year in terms
of publications focusing on
nondialysis CKD
Predicting progression of CKD and
outcomes of patients with CKD has been
the focus of many publications over the
past 2 years. Increasingly, investigators
have identified aspects of kidney disease
that portend poorer outcomes. A series of
papers have described the ability of simple
laboratory parameters to predict progression
to ESRD over 5 years, 4 ’’
and highlighted
that the rate of eGFR decline needs
Key advances
■ Consensus is increasing in the clinical and
scientific community that classification
of chronic kidney disease (CKD) needs
to evolve to a more complex staging
system that includes etiology, albuminuria,
estimates of glomerular filtration rate and
other available parameters 1,4,7
■ More sophisticated methods of
genotyping and phenotyping individuals
have led to an improved ability to predict
outcomes in patients with CKD 2,3,8
■ The SHARP trial determined that a
lipid-lowering strategy safely reduced
atherosclerotic events in patients with
CKD; these findings, which showed that
the benefits were proportional to the lipid
lowering achieved, irrespective of initial
lipid values, have huge implications for
clinical care 10
to be considered in prediction equations, 5
as well as the need to incorporate urine
albumin excretion and estimates of GFR
into risk prediction models 6 in patients
with established CKD. The report of the
consensus conference arranged under the
KDIGO (Kidney Disease Improving Global
Outcomes) organizational banner helped to
consolidate a series of key conceptual issues
relating to prognosis and risk stratification. 7
Another important paper was that by
Isakova et al., who demonstrated the importance
of fibroblast growth factor 23 (FGF23)
in predicting adverse outcomes in patients
with CKD. 8 Levels of FGF23 demonstrated
a stepwise increase in association with
mortal ity and ESRD. Within the context
of our increasing knowledge of the unique
role of FGF23 in cardiac hypertrophy and
potential therapeutic interventions, this
study has refocused the nephrology community
on the utility of newer biomarkers
in risk stratification and in understanding
the underlying biological processes involved
in disease progression.
The importance of well-conducted clinical
trials that answer questions of key importance
cannot be overstated. Two such papers
were published in 2011, one addressing a
new compound that might delay dialysis in
patients with CKD, and the other addressing
atherosclerotic events in patients with CKD.
A study examining the effect of bardoxolone
(an oral antioxidant, anti-inflammatory
modulator) in patients with diabetes and
CKD, demonstrated an improvement in
eGFR at 24 weeks and 52 weeks in the participants.
9 This study is the first to potentially
offer some hope to patients with CKD,
although issues related to mechanism of
NEPHROLOGY
action of the medication, long-term effects
of increasing eGFR (that is, potential for
accelerated progression), and utility in all
clinical circumstances were not addressed
in this phase II study. However, these findings,
which show that therapeutic agents
that might improve kidney function exist,
are a source of optimism for the millions
of patients with CKD.
The SHARP study, an international 5-year
randomized, placebo-controlled trial of
>9,000 patients with CKD, found that active
lipid-lowering treatment (simva statin 20 mg
and ezetimibe 10 mg) was effective in reducing
atherosclerotic events in patients both
on and off dialysis. 10 This study is seminal
in that it is the largest trial ever conducted
in CKD, and enables clini cians to appreciate
the benefit and very low risk profile of
a fixed dose of lipid-lowering medication
for this population. Although the study
was not powered to examine mortality, the
results did demon strate a 17% reduction in
major atherosclerotic events. Publication of
this study in the Lancet further validates the
importance of these findings and the impact
it is likely to have on general care. Moreover,
the consistent finding that for any lowering
of LDL-cholesterol levels, there was a benefit
to patients with CKD similar to that found
in the general population, adds credence to
the hypothesis that atherosclerotic events
can be ameliorated by targeted therapy in
a wide range of patients. The SHARP study
also reminds us that morbidity and mortality
in CKD is more complex than simply
being linked to atherosclerotic events, and
thus highlights that there is more research
to be done.
Overall, 2011 was an astounding year
in terms of publications focusing on nondialysis
CKD. The majority of these papers
are in general medical journals, 1,3,4,8–10 which
is further testimony to the recognition of
the importance of this area of medicine.
The overall message from these studies
is that CKD is important, identi fiable by
simple means, is variable in its expression
and outcomes, and both progressive disease
and associated comorbidi ties are amenable
to thera peutic interventions, which is reassuring
for patients and their caregivers.
Ongoing genomic and proteomic studies will
further unravel the mystery of CKD progression
and outcomes. The breadth and depth
of nephrology insights and understandings
continues to grow, as is evidenced in this
landmark year. With such growth, we would
anticipate an exciting future for both science
and clinical care in the years to come.
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