Stent Placement in Patients With Atherosclerotic Renal Artery Stenosis and Impaired Renal Function A Randomized Trial

Article (PDF Available)inAnnals of internal medicine 150(12):840-8, W150-1 · June 2009with55 Reads
Source: PubMed
Abstract
Little is known about the efficacy and safety of renal artery stenting in patients with atherosclerotic renal artery stenosis (ARAS) and impaired renal function. To determine the efficacy and safety of stent placement in patients with ARAS and impaired renal function. Randomized clinical trial. Randomization was centralized and computer generated, and allocation was assigned by e-mail. Patients, providers, and persons who assessed outcomes were not blinded to treatment assignment. 10 European medical centers. 140 patients with creatinine clearance less than 80 mL/min per 1.73 m(2) and ARAS of 50% or greater. Stent placement and medical treatment (64 patients) or medical treatment only (76 patients). Medical treatment consisted of antihypertensive treatment, a statin, and aspirin. The primary end point was a 20% or greater decrease in creatinine clearance. Secondary end points included safety and cardiovascular morbidity and mortality. Forty-six of 64 patients assigned to stent placement had the procedure. Ten of the 64 patients (16%) in the stent placement group and 16 patients (22%) in the medication group reached the primary end point (hazard ratio, 0.73 [95% CI, 0.33 to 1.61]). Serious complications occurred in the stent group, including 2 procedure-related deaths (3%), 1 late death secondary to an infected hematoma, and 1 patient who required dialysis secondary to cholesterol embolism. The groups did not differ for other secondary end points. Many patients were falsely identified as having renal artery stenosis greater than 50% by noninvasive imaging and did not ultimately require stenting. Stent placement with medical treatment had no clear effect on progression of impaired renal function but led to a small number of significant procedure-related complications. The study findings favor a conservative approach to patients with ARAS, focused on cardiovascular risk factor management and avoiding stenting.

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COMMENTS AND RESPONSES
Determining the Benefits of the New York City
Trans Fat Ban
TO THE EDITOR: Angell and colleagues (1) want to be congratulated
for finding that their own regulatory approach has succeeded—
according to them. The New York City Department of Health and
Mental Hygiene passed a regulation restricting the use of trans fatty
acids (TFAs) in chain restaurants, and the authors have discovered
that—lo and behold!—this law is being obeyed. But what have they
accomplished in terms of public health? That is a difficult question
to answer.
The amount of TFAs in one’s diet is repeatedly referred to as a
“recognized risk factor” for heart disease. However, this assessment is
based entirely on observational dietary studies—and diet is not listed
among the main coronary risk factors. Furthermore, on the basis of
my 20-plus years of practicing internal medicine, I can attest to how
hard it is to significantly reduce lipid levels through diet, despite all
the stringent diet programs we so assiduously distributed to our
at-risk patients. Now, at last, the authors assert that they have found
the culprit: TFAs. They say that by eliminating these heart-attack
generators, we can relax and throw away those statins.
Not so fast. Is there a shred of evidence that decreasing TFA
intake actually lowers lipid levels—much less reduces the toll of
cardiovascular disease? No. So why are the authors trumpeting how
their new regulations have led to restaurant food with “healthier fatty
acid profiles”?
Health issues aside, where will such measures lead us? In the
accompanying editorial (2), Gerberding says, “Unfortunately, relying
on consumers alone to make healthy choices about food intake is a
strategy that has not worked, as our growing obesity epidemic dem-
onstrates.” Since when is “allowing” Americans to choose their own
food a public health strategy? And what does TFA intake have to do
with the obesity epidemic? Not a thing, as I’m sure Gerberding
knows.
If the authors are allowed to merely declare that their govern-
ment regulatory program on TFAs is a success, there are in all like-
lihood more such strategies for “guiding” consumer health choices
coming down the pike, to your local pharmacies and restaurants, and
your kitchens. The authors apparently believe that we cannot be
trusted to figure out our own diet choices regarding our health, and
they nominate the New York Department of Health and Mental
Hygiene to be the food arbiter of first resort. This would be a bad
idea for health and for personal responsibility.
Gilbert L. Ross, MD
American Council on Science and Health
New York, NY 10023
Potential Conflicts of Interest: The American Council on Science and
Health, a nonprofit consumer education organization, accepts no-strings-
attached donations from corporations, individuals, and foundations.
Food-related companies have contributed well under 2% of the Coun-
cil’s budget.
References
1. Angell SY, Silver LD, Goldstein GP, Johnson CM, Deitcher DR, Frieden TR, et al.
Cholesterol control beyond the clinic: New York City’s trans fat restriction. Ann Intern
Med. 2009;151:129-34. [PMID: 19620165]
2. Gerberding JL. Safer fats for healthier hearts: the case for eliminating dietary artificial
trans fat intake [Editorial]. Ann Intern Med. 2009;151:137-8. [PMID: 19620167]
TO THE EDITOR: What Angell and colleagues (1) could not say was
how this initiative has actually helped the citizens of New York. The
presumption is that ridding the food supply of TFAs will reduce the
cholesterol levels of millions of people. Improving the cholesterol
levels should result in reduced cardiovascular disease, but has it?
Because most New Yorkers eat in restaurants, often several times a
week, there should be a significant decrease in the number of heart
attacks and heart attack deaths, right? And certainly, with all the
modern statistical tools we have available and with a precise knowl-
edge of the exact date that the TFA ban went into effect, we must be
able to show the health benefits that accrued from the New York
ban. Surely we can be spared the lame excuse that “cardiovascular
disease is multifactorial; therefore, we can’t really tell whether the
ban worked.” No metrics are in place to measure what should have
been the primary goal of the ban. The persons behind the ban felt
that they could dispense with the trivialities of actually determining
whether their initiative really accomplished anything. The journey is
more important than the destination, as they say. The fact is, there is
nothing in place to “show me the money.”
For 1500 years, the world believed in “spontaneous generation”
simply because the Greek philosophers said it was so. Francis Bacon,
often referred to as the father of the scientific method, didn’t buy it
and effectively said, “Show me the money!” Credibility must be
based on experimentally derived evidence.
The scientific integrity of the United States and its great insti-
tutions is declining because we are associating credibility with insti-
tutions rather than with evidence. We accept notions without de-
manding proof. It may well be that spontaneous generation is real
and that New York’s citizens have benefited from the TFA ban, but
until objectively obtained evidence confirms this, the only ones who
have really benefited are the persons and institutions who have gar-
nered unwarranted praise and free publicity. Consumers should be
served a lot better than that.
Morton Satin, MSc
Salt Institute
Alexandria, VA 22314
Potential Conflicts of Interest: None disclosed.
Reference
1. Angell SY, Silver LD, Goldstein GP, Johnson CM, Deitcher DR, Frieden TR, et al.
Cholesterol control beyond the clinic: New York City’s trans fat restriction. Ann Intern
Med. 2009;151:129-34. [PMID: 19620165]
IN RESPONSE: Regarding Dr. Ross’s comment, evidence supporting
restriction of TFA use is not limited to observational studies. A
multitude of controlled feeding trials (1) have assessed the effect of
TFAs on serum lipid profiles. Meta-analyses of up to 60 of these
trials (2, 3) show a relative increase in low-density lipoprotein cho-
lesterol levels and a decrease in high-density lipoprotein cholesterol
levels when TFAs are consumed, compared with saturated or cis
unsaturated fats. As Gerberding says in her accompanying editorial
(4), the science for eliminating exposure is “rock solid.”
Annals of Internal MedicineLetters
194 © 2010 American College of Physicians
Mr. Satin expresses frustration that measuring the isolated effect
of TFA restrictions may not be possible, even with modern statistical
tools. Unlike biomedical research, evaluation of population-level
health interventions does not always allow for randomized, con-
trolled trials. Once there is scientific consensus that the exposure of
interest is dangerous, such as for lead-based paint, pesticides, or
TFAs, such trials may also be unethical. That said, evaluation is
integral to good public health practice, and the best possible methods
should be used to assess interventions.
Evaluations under way include assessment of replacement prod-
ucts, changes in fatty acid composition of foods, and investigation of
coronary heart disease mortality. We are assessing changes in coro-
nary heart disease risk and in markers of TFA intake coronary by
repeating NYCHANES (New York City’s 2004 Health and Nutri-
tion Examination Survey). The NYCHANES included a representa-
tive sample of sera in repository, which can provide a preintervention
baseline.
In her commentary (4), Gerberding affirms the substantial pub-
lic health risk associated with artificial TFAs but raises concern that
healthier oil supplies are not sufficient for replacement at the na-
tional level. Similar arguments were raised in 2005 at the time of our
proposal. All failed to materialize as practical obstacles. No shortages
of safer replacement products have been reported, and saturated fat
use has declined in at least some areas. Indeed, the food industry
proved efficient when faced with a clear imperative and an appropri-
ate timeline.
Finally, Dr. Ross says that restricting TFA use reduces consumer
choice. We beg to differ. Artificial TFAs were added to restaurant
meals unbeknownst to consumers; menus never offered a choice be-
tween french fries with or without artificial TFA. Industry chose to
use artificial TFAs because of practical industrial advantages. As its
dangers are now apparent, there is no reason not to remove it from
our food.
Sonia Y. Angell, MD, MPH
Lynn Dee Silver, MD, MPH
Gail P. Goldstein, MPH
New York City Department of Health and Mental Hygiene
New York, NY 10007
Potential Conflicts of Interest: None disclosed.
References
1. Panel on Macronutrients. Letter report on dietary reference intakes for trans fatty
acids. In: Institute of Medicine. Dietary Reference Intakes for Energy, Carbohydrate,
Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, DC:
National Academies Pr; 2002.
2. Mensink RP, Zock PL, Kester AD, Katan MB. Effects of dietary fatty acids and
carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and
apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr. 2003;77:
1146-55. [PMID: 12716665]
3. Mozaffarian D, Katan MB, Ascherio A, Stampfer MJ, Willett WC. Trans fatty acids
and cardiovascular disease. N Engl J Med. 2006;354:1601-13. [PMID: 16611951]
4. Gerberding JL. Safer fats for healthier hearts: the case for eliminating dietary artificial
trans fat intake [Editorial]. Ann Intern Med. 2009;151:137-8. [PMID: 19620167]
Reclassification Calculations for Persons With Incomplete
Follow-up
TO THE EDITOR: We applaud Cook and Ridker (1) for their clear
discussion of reclassification measures and recent developments in
judging the incremental value of a biomarker for prediction of out-
come. A key area of application is in cardiovascular disease, in which
the time horizon is typically 10 years. One important problem rec-
ognized by Cook and Ridker is that not all persons will have
follow-up completed until 10 years. Kaplan–Meier curves and Cox
regression analysis were introduced long ago to deal with such cen-
sored observations. Reclassification measures, such as the net reclas-
sification index (NRI) (2), have been proposed for binary data and
currently have no way of incorporating incomplete follow-up. As with
other model performance measures in survival analysis, reclassification
statistics can be estimated at different times during follow-up.
To address the issue of censored data, Cook and Ridker propose
selecting only persons with follow-up complete at a certain time
point (8 years in their example). They included most control partic-
ipants, because 23 611 of 23 792 women had follow-up of at least 8
years, excluding only 181 (1%). But only 560 of 766 women had a
cardiovascular event before 8 years of follow-up, leading to exclusion
of 206 (27%).
We suggest a simple alternative based on the expected number
of case patients and control participants calculated by using the
Kaplan–Meier estimator. This approach was recently found opti-
mum in assessing calibration of survival models (3). It appropriately
handles censored data and does not throw away useful information.
We provide a revision to Figure 1 of the original article (Table)
created with our proposal, with cell entries for case patients and
control participants obtained by multiplying the 10-year Kaplan–
Meier rates by the total persons in each cell at 10 years given in the
original table. We then expect 697 case patients and 23 861 control
participants at 10 years of follow-up.
The reclassification numbers change to some extent. Although
the conclusions remain largely the same in this example (NRI, 9.9%
vs. 9.8% in the original), we recommend our simple estimation pro-
cedure of the NRI for future application with censored observations.
Especially when more censoring occurs early during follow-up, our
approach is attractive. In this case, choosing 1 time point for analysis
can lead to exclusion of many control participants, or relatively many
case patients, making the NRI estimate unstable. Some specific is-
sues, such as bias and precision, require further research. We note
that the asymptotic CI for NRI calculated with the approach out-
lined by Pencina and colleagues (2) is no longer valid for the current
extension. A practical solution would use bootstrap estimation (4),
which is also useful for bias correction (as also suggested by Cook
and Ridker).
Ewout W. Steyerberg, PhD
Erasmus MC University Medical Center Rotterdam
Rotterdam 3015, the Netherlands
Michael J. Pencina, PhD
Boston University
Boston, MA 02215
Potential Conflicts of Interest: None disclosed.
Letters
www.annals.org 2 February 2010 Annals of Internal Medicine Volume 152 • Number 3 195
References
1. Cook NR, Ridker PM. Advances in measuring the effect of individual predictors of
cardiovascular risk: the role of reclassification measures. Ann Intern Med. 2009;150:
795-802. [PMID: 19487714]
2. Pencina MJ, D’Agostino RB Sr, D’Agostino RB Jr, Vasan RS. Evaluating the added
predictive ability of a new marker: from area under the ROC curve to reclassification
and beyond. Stat Med. 2008;27:157-72; discussion 207-12. [PMID: 17569110]
3. Viallon V, Ragusa S, Clavel-Chapelon F, Be´nichou J. How to evaluate the calibra-
tion of a disease risk prediction tool. Stat Med. 2009;28:901-16. [PMID: 19156698]
4. Pepe MS, Feng Z, Gu JW. Comments on ‘Evaluating the added predictive ability of
a new marker: From area under the ROC curve to reclassification and beyond’ by M.
J. Pencina et al., Statistics in Medicine (DOI: 10.1002/sim.2929). Stat Med. 2008;27:
173-81. [PMID: 17671958]
IN RESPONSE: We thank Drs. Steyerberg and Pencina for bringing
up an important point about evaluating reclassification measures in
the presence of survival data. When the outcome is time to an event,
such as a cardiovascular event, care must be taken to accommodate
censoring. The reclassification calibration statistic can easily be cal-
culated by using survival data, as indicated in our article. The
Kaplan–Meier estimate of the event rate as of 10 years, for example,
can be used to obtain the expected number of events within each cell
of the reclassification table. D’Agostino and Nam (1) suggest that
with survival data, the degrees of freedom should be k1 rather
than k2, where kin the setting of reclassification is the number of
cells containing at least 20 persons.
The use of survival data is more problematic for the NRI and
integrated discrimination improvement, which both rely on case–
control status. A similar problem occurs for the c-statistic, but meth-
ods to accommodate survival data have been established (2). For the
NRI, Drs. Steyerberg and Pencina propose using the expected num-
ber of cases based on the Kaplan–Meier estimate in each cell—the
same calculation needed for the reclassification calibration statistic.
Although an estimated SE is not currently available for this measure,
a CI and an SE can be determined by using bootstrap samples.
We suggest that both the reclassification calibration statistic and
the NRI be computed for reclassification tables, even in the presence
of survival data.
Nancy R. Cook, ScD
Paul M Ridker, MD
Brigham and Women’s Hospital
Boston, MA 02215
Potential Conflicts of Interest: None disclosed.
Table. Reclassification Table Comparing 10-Year Risk Strata for Models That Include Risk Factors for Cardiovascular Disease in
the Women’s Health Study With and Without SBP*
Model Without SBP Model With SBP,
n (%)
Total,
n (%)
Reclassified Into New Risk
Category,
%
0% to <5% 0% to 5% 5% to 10% 10% to 20% >20% Lower Higher Total
Persons included 20 372 (96.6) 696 (3.3) 23 (0.1) 0.0 (0.0) 21 091 (85.9) 0.0 3.4 3.4
Case patients† 264.8 (84.8) 47.3 (15.2) 0.0 (0.0) 0.0 (0.0) 312.2 (44.8) 0.0 15.2 15.2
Control participants† 20 107.2 (96.8) 648.7 (3.1) 23.0 (0.1) 0.0 (0.0) 20 778.8 (87.1) 0.0 3.2 3.2
Observed risk, %‡ 1.3 6.8 0.0
5% to <10%
Persons included 635 (26.6) 1441 (60.3) 307 (12.8) 7 (0.3) 2390 (9.7) 26.6 13.1 39.7
Case patients† 27.9 (14.3) 121.0 (61.8) 44.8 (22.9) 1.2 (0.6) 196.0 (28.1) 14.3 23.5 37.8
Control participants† 607.1 (27.7) 1320.0 (60.2) 262.2 (11.9) 5.8 (0.3) 2194.0 (9.2) 27.7 12.2 39.9
Observed risk, %‡ 4.4 8.4 14.6 17.5
10% to <20%
Persons included 4.0 (0.5) 204 (25.0) 519 (63.5) 90 (11.0) 817 (3.3) 25.5 11.0 36.5
Case patients† 0.0 (0.0) 8.8 (7.7) 74.2 (65.2) 30.8 (27.1) 113.8 (16.3) 7.7 27.1 34.8
Control participants† 4.0 (0.6) 195.2 (27.8) 444.8 (63.2) 59.2 (8.4) 703.2 (2.9) 28.3 8.4 36.8
Observed risk, %‡ 0.0 4.3 14.3 34.2
>20%
Persons included 0.0 (0.0) 2.0 (0.8) 54 (20.8) 204 (78.5) 260 (1.1) 21.5 0.0 21.5
Case patients† 0.0 (0.0) 0.0 (0.0) 14.0 (18.9) 60.0 (81.1) 74.0 (10.6) 18.9 0.0 18.9
Control participants† 0.0 (0.0) 2.0 (1.1) 40.0 (21.5) 144.0 (77.4) 186.0 (0.8) 22.6 0.0 22.6
Observed risk, % 0.0 25.9 29.4
Total
Persons included 21 011 (85.6) 2343 (9.5) 903 (3.7) 301 (1.2) 24 558 (100.0)
Case patients† 294.2 (42.3) 178.1 (25.6) 132.7 (19.1) 91.8 (13.2) 695.9 (100.0)
Control participants,† 20 716.8 (86.8) 2164.9 (9.1) 770.3 (3.2) 209.2 (0.9) 23 862.1 (100.0)
Observed risk, %‡ 1.4 7.6 14.7 30.5
SBP systolic blood pressure.
*Using the 10-year Kaplan–Meier estimates to estimate the number of case patients and control participants. Reclassification improved by 10.5% in case patients (124 to
51 of 696), whereas classification worsened in control participants by 0.6% (848 to 999 of 23 861), leading to a net reclassification improvement of 9.9%.
Originally, case patients and control participants were counted at 8 years of follow-up, ignoring censored observations. Here, we use the 10-year Kaplan–Meier estimates
to estimate the number of case patients and control participants (e.g., 1.3% 20 372 264.8 cases expected at 10-year follow-up).
Observed risk at 10 years is estimated from the Kaplan–Meier curve by using observations in each cell.
Letters
196 2 February 2010 Annals of Internal Medicine Volume 152 • Number 3 www.annals.org
References
1. D’Agostino RB, Nam BH. Evaluation of the performance of survival analysis mod-
els: discrimination and calibration measures. In: Balakrishan N, Rao CR, eds. Hand-
book of Statistics, 23. Philadelphia: Elsevier; 2005:1-25.
2. Harrell FE Jr. Regression Modeling Strategies. New York: Springer; 2001.
Stent Placement in Patients With Atherosclerotic Renal
Artery Stenosis and Impaired Renal Function
TO THE EDITOR: When the results of a randomized trial disagree
with clinical experience and previous publications, their validity mer-
its critical examination. In the STAR (STent placement and blood
pressure and lipid-lowering for the prevention of progression of renal
dysfunction caused by Atherosclerotic ostial stenosis of the Renal
artery) trial assessing the efficacy of renal artery stenting, Bax and
colleagues reported no benefit and recommended avoiding stenting
in patients with renal artery stenosis (1). This could lead to denial of
the procedure, by physicians and by managed care organizations, to
patients who truly need it.
We have personally observed many patients who, after renal
artery angioplasty with or without stenting, experienced rapid ame-
lioration of such problems as refractory hypertension, congestive
heart failure, and renal insufficiency. Thus, it is inconceivable to us,
and to many others, that stenting is of no benefit. Unfortunately,
there is also no doubt that stenting is overused, often done in cases
where it is unlikely to benefit.
Why did this randomized trial show no benefit? First, among
the patients randomly assigned to the stenting group and in-
cluded in the intention-to-treat analysis, 40 of 64 (62.5%) were
unlikely to benefit because 12 had stenoses less than 50% and
were not even stented; 22 had stenoses of 50% to 70%, which
usually is not hemodynamically significant (even some stenoses of
70% to 90% are not hemodynamically significant [2]); and stent-
ing was not performed for various reasons in 6 others. Unfortu-
nately, hemodynamic significance of the stenoses was not as-
sessed. Second, all patients were required to have a treated blood
pressure less than 140/90 mm Hg on entry, thus excluding pa-
tients with resistant hypertension, who are more likely to have
true renovascular hypertension and ischemic nephropathy. Third,
there is a major unmentioned bias: Patients strongly believed to
have true renovascular hypertension, who would be the most
likely to benefit, are generally referred for stenting rather than
being entered into a randomized study that could deny them the
procedure. There is no easy answer for this problem, and in such
situations, a randomized trial might be the wrong type of study.
Extrapolation of the results of this study to patients with un-
equivocal renovascular hypertension and ischemic nephropathy is
unwarranted and wrong. Clearly, there are cases where the wisdom
of stenting is unclear, but this study did not address that important
question.
The overuse of renal artery angioplasty and stenting clearly
merits condemnation. However, the benefit of the procedure in
appropriate patients should not be withheld on the basis of this
trial. Instead, clarification of the indications for stenting is
needed.
Samuel J. Mann, MD
Thomas A. Sos, MD
Weill Cornell Medical College
New York, NY 10021
Potential Conflicts of Interest: None disclosed.
References
1. Bax L, Woittiez AJ, Kouwenberg HJ, Mali WP, Buskens E, Beek FJ, et al. Stent
placement in patients with atherosclerotic renal artery stenosis and impaired renal
function: a randomized trial. Ann Intern Med. 2009;150:840-8, W150-1. [PMID:
19414832]
2. Simon G. What is critical renal artery stenosis? Implications for treatment. Am J
Hypertens. 2000;13:1189-93. [PMID: 11078179]
TO THE EDITOR: We read with interest the randomized trial on
renal artery stenting by Bax and colleagues (1). We agree that ran-
domized trials are ultimately the way to prove or disprove the use-
fulness of renal artery angioplasty and stenting in the treatment of
renal artery stenosis. However, we are concerned that, because of
several issues, this particular study will do neither.
First, the abstract is inconsistent. The Results section, which
should essentially reflect a nonsignificant reduction in the primary
end point and no significant difference in the secondary end point, is
not adequately summarized, and the Conclusion section does not
reflect the fact that, despite the unusually high number and severity
of procedure-related complications in the stenting group, mortality
did not differ between the 2 groups. Because the abstract is the most
widely disseminated part of any article, these shortcomings are very
unfortunate.
Second, as acknowledged by the authors and in the editors’
notes, the study was underpowered because the rate of events in the
control group was lower than anticipated. This impairs the study’s
ability to detect a real difference between renal artery stenting and
medical therapy (2), although it is noteworthy that the point esti-
mate of the hazard ratio for the primary end point (0.73) favors
stenting. Moreover, the evidence for renal revascularization therapy
to halt progression of renal insufficiency is not solid and, as such,
choosing an increase in creatinine as the primary end point was not
a good choice.
Finally, the significance of renal artery stenosis was not physio-
logically assessed—a widespread problem in current randomized tri-
als of renal stenting (3). Indeed, patients with renal stenosis severity
as low as 50% were included, when the evidence suggests that ste-
noses less than 70% are not hemodynamically significant (4). Inclu-
sion criteria contained no stringent requirement of therapy with at
least 3 antihypertensives, as required by the American College of
Cardiology/American Heart Association guidelines (5). These factors
may also have biased the study results toward showing no benefit
with renal stenting.
In summary, every piece of evidence that contributes to our
better understanding of the optimal therapy of renal artery stenosis is
welcome, but only if the evidence is clear. Unfortunately, the study
by Bax and colleagues raises more questions than provides answers
and will make it harder for other investigators to obtain support for
future trials addressing the issue.
Letters
www.annals.org 2 February 2010 Annals of Internal Medicine Volume 152 • Number 3 197
Ion S. Jovin, MD, ScD
On Topaz, MD
Virginia Commonwealth University
Richmond, VA 23284
Potential Conflicts of Interest: None disclosed.
References
1. Bax L, Woittiez AJ, Kouwenberg HJ, Mali WP, Buskens E, Beek FJ, et al. Stent
placement in patients with atherosclerotic renal artery stenosis and impaired renal
function: a randomized trial. Ann Intern Med. 2009;150:840-8, W150-1. [PMID:
19414832]
2. Szczech LA, Coladonato JA, Owen WF Jr. Key concepts in biostatistics: using
statistics to answer the question “is there a difference?”. Semin Dial. 2002;15:347-51.
[PMID: 12358639]
3. Schwarzwa¨lder U, Zeller T. Critical review of indications for renal artery stenting: do
randomized trials give the answer? Catheter Cardiovasc Interv. 2009;74:251-6.
[PMID: 19434748]
4. Schoenberg SO, Bock M, Kallinowski F, Just A. Correlation of hemodynamic
impact and morphologic degree of renal artery stenosis in a canine model. J Am Soc
Nephrol. 2000;11:2190-8. [PMID: 11095642]
5. Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, et al;
American Association for Vascular Surgery. ACC/AHA 2005 guidelines for the
management of patients with peripheral arterial disease (lower extremity, renal, mesen-
teric, and abdominal aortic): executive summary a collaborative report from the Amer-
ican Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardio-
vascular Angiography and Interventions, Society for Vascular Medicine and Biology,
Society of Interventional Radiology, and the ACC/AHA Task Force on Practice
Guidelines (Writing Committee to Develop Guidelines for the Management of Pa-
tients With Peripheral Arterial Disease) endorsed by the American Association of Car-
diovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute;
Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular
Disease Foundation. J Am Coll Cardiol. 2006;47:1239-312. [PMID: 16545667]
IN RESPONSE: Our study showed that stent placement incurs costs
and complications for an at best uncertain benefit in patients with
impaired renal function and atherosclerotic renal artery stenosis
(ARAS). For these patients, stenting remains a subject of research.
We want to emphasize that we focused our study on impaired renal
function and ARAS and therefore do not make statements about other
categories of patients, such as those with renovascular hypertension,
therapy-refractory hypertension, or congestive heart failure.
As discussed in our article, the lower-than-anticipated event rate
reduced the power of our study, and we might therefore be dealing
with a chance finding. In the meantime, the ASTRAL (Angioplasty
and Stenting for Renal Artery Lesions) study (1) from the United
Kingdom, which includes more than 800 patients, has found similar
results and did not show any effect in predefined subgroup analysis,
such as severe renal dysfunction or severe or bilateral renal artery
stenosis.
The statement by Drs. Mann and Sos that patients are unlikely,
a priori, to benefit from stent placement is simplistic and is not
correct, because the different categories stated largely overlap.
Both Drs. Mann and Sos and Drs. Jovin and Topaz suggest that
poor patient selection (for not using functional stenosis tests) and
including patients with stenoses of 50% to 70% explains the negative
results. The hypothesis that patients with more severe ARAS would
benefit more from stent placement has, however, not been demon-
strated in terms of renal function. In fact, the severity of the stenosis
is not correlated with renal function in patients with ARAS and
impaired renal function (2), and it is neither a predictor of progres-
sion of renal failure nor a predictor of outcome after revascularization
(3–5). Yet, most of our patients (67%) had stenosis greater than 70%
to the most affected kidney. When we designed our study back in 1999,
a reduction in luminal diameter of 50% or more (corresponding to a
surface reduction 70%) was widely considered to be clinically signifi-
cant (6). Although our insight on the relationship between stenosis se-
verity and degree of renin release by the poststenotic kidney and reno-
vascular hypertension may have improved in the last decade, functional
tests have not been proven to predict favorable outcome after stent place-
ment as far as renal function is concerned. This underscores the fact that
the pathophysiology of renal failure in this group of patients is extremely
complex. In addition to reduced blood flow, renal function in these
patients is also the dependent on presence of small-vessel disease, glo-
merulosclerosis, and renal fibrosis.
Although there may be some criticism, our study shows that indis-
criminate widespread introduction of stent placement without proper
scientific evaluation is unjustified, costly, and dangerous for patients.
Liesbeth Bax, MD, PhD
Willem P.T.M. Mali, MD, PhD
University Medical Center Utrecht
3584 CX Utrecht, the Netherlands
Jaap J. Beutler, MD, PhD
Jeroen Bosch Hospital
5211 NL ’s Hertogenbosch, the Netherlands
Potential Conflicts of Interest: None disclosed.
References
1. Wheatley K, Ives N, Gray R, Kalra PA, Moss JG, Baigent C, et al; ASTRAL
Investigators. Revascularization versus medical therapy for renal-artery stenosis. N Engl
J Med. 2009;361:1953-62. [PMID: 19907042]
2. Farmer CK, Cook GJ, Blake GM, Reidy J, Scoble JE. Individual kidney function in
atherosclerotic nephropathy is not related to the presence of renal artery stenosis.
Nephrol Dial Transplant. 1999;14:2880-4. [PMID: 10570091]
3. Suresh M, Laboi P, Mamtora H, Kalra PA. Relationship of renal dysfunction to
proximal arterial disease severity in atherosclerotic renovascular disease. Nephrol Dial
Transplant. 2000;15:631-6. [PMID: 10809803]
4. Cheung CM, Wright JR, Shurrab AE, Mamtora H, Foley RN, O’Donoghue DJ, et
al. Epidemiology of renal dysfunction and patient outcome in atherosclerotic renal
artery occlusion. J Am Soc Nephrol. 2002;13:149-57. [PMID: 11752032]
5. Wright JR, Shurrab AE, Cheung C, Waldek S, O’Donoghue DJ, Foley RN, et al.
A prospective study of the determinants of renal functional outcome and mortality in
atherosclerotic renovascular disease. Am J Kidney Dis. 2002;39:1153-61. [PMID:
12046025]
6. Leertouwer TC, Gussenhoven EJ, Bosch JL, van Jaarsveld BC, van Dijk LC, Dei-
num J, et al. Stent placement for renal arterial stenosis: where do we stand? A meta-
analysis. Radiology. 2000;216:78-85. [PMID: 10887230]
CLINICAL OBSERVATION
Colored Sweat Caused by Pseudochromhidrosis
Background: Pseudochromhidrosis and chromhidrosis are con-
ditions associated with colored sweat. Pseudochromhidrosis is pro-
duction of colorless sweat that becomes colored when it reaches the
skin and combines with other agents, whereas chromhidrosis is a rare
condition associated with production of colored sweat by apocrine
sweat glands.
Letters
198 2 February 2010 Annals of Internal Medicine Volume 152 • Number 3 www.annals.org
Objective: To report a case of a patient with pseudochromhidrosis.
Case Report: A 36-year-old white man presented with a 2-year
history of brown-black sweat on his face, neck, and thorax. Colored
sweat was intermittent and was not related to a specific time of day,
body position, or food consumption but was pronounced after par-
ticipation in sports. It was not accompanied by odor, fever, local or
systemic symptoms, or changes in the patient’s skin appearance. The
sweat dyed his clothes (Figure), pillows, and sheets. He did not use
deodorants. His medical history was unremarkable, and he reported
no trauma, known allergy, or drug use. The colored sweat was not
associated with clothing or exposure to chemicals or dyes. Factitious
disorders were ruled out after psychiatric evaluation.
Complete blood count, prothrombin time, partial thromboplas-
tin time, international normalized ratio, biochemistry, and urinan-
alysis were normal. The toxicology examination was negative. Deter-
mination of 5-hydroxyindoleacetic acid to rule out the carcinoid
syndrome and of homogentisic acid to rule out alkaptonuria and
ochronosis in a 24-hour urine collection were normal. Gram stains of
smears obtained from the affected sites for pathogen isolation were
negative. Computed tomography of the abdomen and indium-111
pentetreotide scintigraphy (Octreoscan, Covidien, Mansfield, Massa-
chusetts), which we performed to further examine the possibility of
the carcinoid syndrome, were normal.
The patient underwent skin biopsy from the frontal thorax.
Histologic examination after periodic acid–Schiff, Giemsa, and
Gram staining revealed the presence of bacteria with a fibrillary and
diphtheroid shape type “Y,” which is characteristic of Corynebacte-
rium. Small gatherings of atrophic, cystically dilated hidropoietic
glands surrounded by infiltration with inflammatory cells were
found; no lipofuscins were found in the sweat glands, which ruled
out chromhidrosis. Thus, the diagnosis of pseudochromhidrosis due
to skin infection with Corynebacterium was confirmed. The patient
was treated with oral erythromycin, 250 mg 3 times daily for 10
days, combined with topical application of erythromycin gel. Com-
plete resolution was obtained at 7 days, and the disorder did not
recur in the next year.
Discussion: Pseudochromhidrosis is production of colorless
sweat that becomes colored when it reaches the skin and combines
with other agents, usually chromogenic bacteria (Corynebacterium
and Pieridae species) or chromogen material, such as extrinsic dyes
and paints (bromophenol blue or copper) (1).
Chromhidrosis is a rare condition associated with production of
colored sweat by apocrine sweat glands. The disease is more common
in black persons. The colored sweat is frequently confined to the face
and axillae and occasionally to the abdomen, chest, thighs, groin,
and genitalia. Cases of red, blue, green, yellow, and black sweat have
been reported (2, 3). Chromhidrotic apocrine glands are character-
ized by deposition of lipofuscins in a higher-than-normal concentra-
tion or a higher-than-normal state of oxidation of unknown cause.
The diagnosis is made by examination of skin biopsies obtained
from the affected sites by ultraviolet light at 360 nm (Wood’s lamp)
for the presence of lipofuscins, which have a yellowish to green ap-
pearance. An even rarer condition is chromhidrosis due to produc-
tion of colored sweat by the eccrine sweat glands after ingestion of
certain dyes or drugs.
The differential diagnosis includes bleeding disorders, hyperbi-
lirubinemia, alkaptonuria, ochronosis, the carcinoid syndrome, der-
matitis simulate, colonization or infection with Pseudomonas species,
chromhidrosis, pseudochromhidrosis, poisoning, and copper expo-
sure (4, 5).
George S. Panagoulias, MD
Christos St. Basagiannis, MD
Nicholas Tentolouris, MD
Athens University Medical School, Laiko General Hospital
Athens GR-11527, Greece
Evgenia Stavropoulou, MD
Lazaros Karnesis, MD
401 General Military Hospital of Athens
Athens GR-11525, Greece
Potential Conflicts of Interest: None disclosed.
References
1. Thami GP, Kanwar AJ. Red facial pseudochromhidrosis. Br J Dermatol. 2000;142:
1219-20. [PMID: 10848751]
2. Hill S, Duffill M, Lamont D, Rademaker M, Yung A. Pseudochromhidrosis: blue
discolouration of the head and neck. Australas J Dermatol. 2007;48:239-41. [PMID:
17956484]
3. Wyrick K, Cragun T, Russ B, Royer MC. Atypical chromhidrosis: a case report of
orange sweat. Cutis. 2008;81:167-70. [PMID: 18441771]
4. Allegue F, Hermo JA, Fachal C, Alfonsı´n N. Localized green pigmentation in a
patient with hyperbilirubinemia. J Am Acad Dermatol. 1996;35:108-9. [PMID:
8682944]
5. Albers SE, Brozena SJ, Glass LF, Fenske NA. Alkaptonuria and ochronosis: case
report and review. J Am Acad Dermatol. 1992;27:609-14. [PMID: 1401313]
CORRECTIONS
Correction: Screening for Breast Cancer
There is an error in the recent U.S. Preventive Services Task
Force recommendation statement on breast cancer screening (1).
Figure. Brown sweat in a patient with pseudochromhidrosis.
The patient’s shirt is dyed by brown sweat due to infection with Coryne-
bacterium. He was successfully treated with oral erythromycin, 250 mg 3
times daily for 10 days, combined with topical erythromycin gel.
Letters
www.annals.org 2 February 2010 Annals of Internal Medicine Volume 152 • Number 3 199
Lines 7 to 8, page 719, right column, should say “...increases
steeply with age, starting in the 40s.” This has been corrected in the
online version.
Reference
1. US Preventive Services Task Force. Screening for breast cancer: U.S. Preventive
Services Task Force recommendation statement. Ann Intern Med. 2009;151:716-26,
W-236. [PMID: 19920272]
Correction: Probiotics for Ulcerative Colitis
In the letter by Conen and colleagues (1) on probiotics for
ulcerative colitis, the authors should be listed as follows:
Anna Conen, MD
Stefan Zimmerer, MD
Andrej Trampuz, MD
Reno Frei, MD
Manuel Battegay, MD
Luigia Elzi, MD, MSc
University Hospital Basel
4031 Basel, Switzerland
This has been corrected in the online version.
Reference
1. Conen A, Zimmerer S, Trampuz A, Frei R, Battegay M, Elzi L. A pain in the neck:
probiotics for ulcerative colitis [Letter]. Ann Intern Med. 2009;151:895-7. [PMID:
20008769]
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Letters
200 2 February 2010 Annals of Internal Medicine Volume 152 • Number 3 www.annals.org
    • "[12] Balk et al. [13] demonstrated a weak evidence that no large differences in mortality rates or cardiovascular events between medical and revascularization therapies. Bax et al. [14] suggested that interventions were associated with serious complications. In addition, current randomized controlled trials comparing percutaneous angioplasty and optimal medical therapy did not prove the distinct advantages of revascularization. "
    Full-text · Article · Jan 2016
    • "The presence of a renal artery significant stenosis was defined as having a stenosis ≥50%, criteria from the stenting in renal dysfunction caused by atherosclerotic RAS. [4] Further, according to laboratory and clinical researches of RAS, [5,6] patients would be graded as severe lesion (RAS ≥ 80%), moderate lesion (50%≤RAS < 80%), mild lesion (50%>RAS > 0), and normal artery (RAS = 0), respectively. "
    [Show abstract] [Hide abstract] ABSTRACT: The decrease of glomerular filtration rate has been theoretically supposed to be the result of low perfusion in renal artery stenosis (RAS). But the gap between artery stenosis and the glomerular filtration ability is still unclear. Patients with selective renal artery angiogram were divided by the degree of renal artery narrowing, level of estimated glomerular filtration rate (eGFR), respectively. The different levels of eGFR, renal microcirculation markers, and RAS severity were compared with each other, to determine the relationships among them. A total of 215 consecutive patients were enrolled in the prospective cohort study. Concentrations of microcirculation markers had no significant difference between RAS group (RAS ≥ 50%) and no RAS group (RAS < 50%) or did not change correspondingly to RAS severity. The value of eGFR in RAS group was lower than that in the no RAS group, but it did not decline parallel to the progressive severity of RAS. The microcirculation markers presented integral difference if grouped by different eGFR level with negative tendency, especially that plasma cystatin C (cysC) and urinary microalbumin to creatinine ratio (mACR) increased with the deterioration of eGFR, with strong (r = -0.713, P < 0.001) and moderate (r = -0.580, P < 0.001) correlations. In the subgroup analysis of severe RAS (RAS ≥ 80%), the levels of plasma cysC and urinary mACR demonstrated stronger negative associations with eGFR, (r = -0.827, P < 0.001) and (r = -0.672, P < 0.001) correlations, respectively. Severity of RAS could not accurately predict the value of eGFR, whereas microcirculation impairment may substantially contribute to the glomerular filtration loss in patients with RAS.
    Full-text · Article · Mar 2015
    • "The heterogeneity was assessed using I 2 values, and sensitivity analysis was performed to explain the heterogeneity where present. Table 2 Quality assessment of included studies Cooper 2014 ASTRAL 2009 Jaarsveld 2000 Bax 2009 Webster 1998 Plouin 1998 "
    [Show abstract] [Hide abstract] ABSTRACT: Our aim is to compare the efficacy of revascularization versus medical therapy in patients with Atherosclerotic renal artery stenosis (ARAS). ARAS is the most common cause of secondary hypertension and is associated with several complications such as renal failure, coronary artery disease, cardiac destabilization and stroke. Medical therapy is the cornerstone for management of ARAS; however, numerous trials have compared medical therapy with revascularization in the form of percutaneous transluminal renal angioplasty with or without stenting (PTRA or PTRAS). Medline (PubMed and Ovid SP), Embase ,Cochrane Central Register of Controlled Clinical Trials(CENTRAL) and Cochrane Database of Systematic Review (CDSR) were searched till present (November 2013) to identify clinical trials where medical therapy was compared with revascularization (PTRA or PTRAS). We performed a Meta –analysis using a random effects model. The heterogeneity was assessed using I2 values. The initial database search identified 540 studies and 7 Randomized controlled trials (RCT’s) and 2139 patients were included in the final analysis. Angioplasty with or without stenting was not superior to medical therapy with respect to any outcome. The incidence of non-fatal MI was 6.74% in both the stenting and medical therapy group (OR=0.998, 95% CI: 0.698-1.427, p=0.992) and incidence of renal events in stenting population was found to be 19.58% vs 20.53% in medical therapy (OR=0.945, 95% CI: 0.755-1.182, p=0.620). In conclusion, PTRA or PTRAS does not improve outcomes when compared with medical therapy in ARAS patients. Future studies should investigate to identify patient sub-groups that may benefit from such an intervention.
    Full-text · Article · Oct 2014
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