C.K.D. Volume 1, Number 3
THE JOURNAL OF CHRONIC KIDNEY DISEASE
Early referral of patients with kidney
disease: overcoming the obstacles
Current care of patients with
patients chronic kidney disease:
Opportunities for improvement
with chronic One-on-One:
An interview with Gerald Bernstein, MD, on
kidney the care of the diabetic nephropathy patient:
a team effort toward optimal outcomes.
disease Lit Review:
Selected papers from the literature
Scarring may play major role
Diagnostic Challenge: in transplant rejection
See page 30 to review Your Opinion:
Treatment of hypertension
this puzzling case.
Table of Contents
Editorial: Early referral of patients with kidney disease: 3
overcoming the obstacles
By Steven Fishbane, MD, and Allen R. Nissenson, MD
Current care of patients with chronic kidney disease: 7
Opportunities for improvement
By Allen R. Nissenson, MD, and Brian J.G. Pereira, MD, MBA
One-on-One: An interview with Gerald Bernstein, MD, on the
care of the diabetic nephropathy patient: a team
effort toward optimal outcomes.
Perspectives on diabetic nephropathy 15
By Eli A. Friedman, MD
Lit Review: Remission and regression in the nephropathy of type 1
diabetes when blood pressure is controlled aggressively
What’s New: Scarring may play major role in transplant rejection 24
Your Opinion: Treatment of hypertension 28
Diagnostic Challenge: Submitted by Jill Lindberg, MD
Steven Fishbane, MD
Mineola, New York
Editorial Allen R. Nissenson, MD
Los Angeles, California
Steven Fishbane, MD Early referral of patients with
Mineola, New York
kidney disease: overcoming the obstacles
Allen R. Nissenson, MD
Los Angeles, California
pproximately 6.2 million Americans have chronic kidney disease (CKD),1 and
care for these patients is often less than ideal.2 Medical management of CKD
Editorial Advisory Board
requires attention to a variety of interrelated problems that have a progressive
Anatole Besarab, MD
Morgantown, West Virginia
impact on patients’ health. For example, anemia and cardiovascular disease
(CVD), both common in CKD,2—4 are interrelated.2 Yet both are inadequately treated in many
W. Kline Bolton, MD patients.2, 5, 6 Anorexia and malnutrition are integral parts of the spectrum of conditions asso-
Charlottesville, Virginia ciated with CKD, yet patients rarely are referred for dietary consultation.7 In the latter stages
David N. Churchill, MD of CKD, planning for and placing vascular access are vitally important, yet most patients
Hamilton, Ontario, Canada start dialysis without a functioning permanent vascular access.7 These examples illustrate
the need for improvement in CKD care.
Robert N. Foley, MD
Salford, United Kingdom
An important factor contributing to these less-than-ideal statistics may be delayed referral
Raymond Hakim, MD, PhD of patients by primary care physicians (PCPs) to nephrologists. In fact, many patients never
Nashville, Tennessee see a nephrologist until the 3 months leading up to dialysis initiation.7 This article explores
reasons for delayed referral, as well as potential solutions.
Annamaria Kausz, MD
Advantages of nephrologist care
Alan S. Kliger, MD Why is early referral important? What data support the hypothesis that care by nephro-
New Haven, Connecticut
logists offers advantages to patients with CKD?
Adeera Levin, MD
Vancouver, British Columbia, Canada Sesso and Belasco8 evaluated the effect of late diagnosis of CKD on mortality risk. They
found that late diagnosis led to a decrease in 6-month survival—from 87% to 69% (P<0.01).
Jill Lindberg, MD
Similarly, studies indicate a 6-fold increase in hospital days with late referral,9 as well as
New Orleans, Louisiana
lengthening of emergency treatment by 2- to 10-fold in inpatient stay over elective care.10
Roger London, MD Other data indicate that failure to refer to a nephrologist adversely affects likelihood of vascu-
White Plains, New York lar access placement, need for emergency dialysis, hypertension and anemia management,
Brian J.G. Pereira, MD, DM, MBA and risk of pulmonary edema.9, 11
Taken together, a large number of studies are remarkably consistent in the ﬁnding of
Richard A. Sherman, MD important beneﬁts when nephrologists are involved early in the care of patients with CKD.
New Brunswick, New Jersey
Although none of these studies are randomized clinical trials, the trend is compelling.
John C. Stivelman, MD
Seattle, Washington Reasons for delayed referral
PCPs choose to refer patients to specialists based on their assessment of patients’ needs
Paul Zabetakis, MD
Oak Park, Illinois and their level of conﬁdence in their ability to adequately meet those needs. Until recently,
the PCP had complete autonomy in referral decisions. The introduction of managed care
plans as payers for primary care created obstacles to specialist referral.7,12 The administrative
Publishing Staff processes set up by managed care companies undoubtedly have contributed to delayed
David Dunn referral to nephrologists.
In addition to managed care issues, a variety of other factors affect nephrology referral
Keith J. Croes
Editorial Director (Table 1). Some patients may have entered a late stage of disease by the time they see a PCP.
For example, a young patient with immunoglobulin-A nephropathy may not be aware that
Norma Padilla, PhD he has the disease until kidney function is severely diminished.9 Indeed, CKD is often
Director, Scientiﬁc Affairs
asymptomatic even as it progresses, and perhaps is more likely to be detected earlier in
Kerry Mariani older individuals than in young, healthy people.
Senior Project Director
Project Director, Scientiﬁc Affairs
Sandra Schaller CKD—The Journal of Chronic Kidney Disease (ISSN 1532-4419) is published quarterly by HealthVizion Communications, Inc.,
Art Director and sponsored by Amgen Inc. Copyright 2002 HealthVizion Communications. All rights reserved.
Address correspondence and request for reprints to the Editorial Director, HealthVizion Communications,
20 Waterview Blvd., Parsippany, NJ 07054-1295; fax: 973-263-3952.
Table 1. Factors That Contribute to Late This problem could be solved if laboratories were
Referral to Nephrologists to report both SCr and Ccr results. Laboratories could
utilize the Cockcroft-Gault formula, which has an 84%
Managed care limitations on specialty referral correlation with measured Ccr,13 and provide Ccr esti-
Late presentation to the PCP mates in their standardized reports. Except for the
patient’s weight, the laboratory has access to all the
PCPs not recognizing that kidney disease is data necessary to do this. The Ccr estimate, therefore,
present because of: could be reported as a range instead of a single ﬁgure.
— failure to recognize CKD in older and smaller
For example, in the case discussed above, the SCr level
patients with normal serum creatinine levels
of 1 mg/dL could be reported with a likely Ccr range
— failure to appropriately screen high-risk patients, of 33 to 66 mL/min for patients weighing 40 to 80 kg.
such as those with diabetes mellitus or Alternatively, a “normogram” could be displayed.
Knowledge of CKD-related issues extends also to the
PCPs not fully understanding CKD treatment issues
and the importance of CKD-related complications PCP’s ability to identify patients who need appropriate
screening. For example, PCPs may overlook micro-
PCPs being unaware of the incremental beneﬁt of albumin testing in patients with diabetes mellitus, or
nephrology consultation SCr levels and urinalysis in patients with hypertension.
PCP’s fear of loss of control over their patient A renal sonogram may be overlooked for the adult
child of a patient with polycystic kidney disease.
PCP’s negative evaluation of previous CKD patient
referral to nephrologists Even when PCPs recognize that CKD is present, they
may have incomplete knowledge of how it should be
Inadequate communication by nephrologists
monitored and treated. The importance of anemia,
Patient reluctance to see another doctor malnutrition, early bone disease, and vascular access
planning may be underappreciated, leading to late
To get an idea of the relative weight PCPs assign referral to the nephrologist.
to the various factors involved in referral decisions,
we conducted a survey (unpublished) of 105 PCPs Nephrologist response
from Long Island, NY. Seventy-three provided detailed PCPs often indicate that, after referring patients with
explanations of their perception of the role of early CKD to nephrologists, patients sometimes report
nephrology consultation in CKD patients. Fifty-one that nephrologists express bewilderment as to why a
of these PCPs reported that they occasionally referred patient not needing dialysis is being referred to them.
patients late in the course of CKD. Table 2 lists some (Many of the PCPs in our survey described such
of the reasons reported by the respondents. experiences.) Why would nephrologists react this way?
It seems clear that nephrologists could do much to con-
Inadequate knowledge of issues tribute meaningfully to the care of such patients.
Among the factors that can potentially delay referral
to the nephrologist is an inadequate knowledge of Two factors may help explain this response. First,
CKD-related issues among some PCPs. The PCP may some nephrologists may not be sufﬁciently aware of
fail even to recognize that CKD is present. Many PCPs the important purpose of consultation in this setting,
rely solely on serum creatinine (SCr) levels as a screen from the standpoints both of medical care and of
for kidney disease, despite the important diagnostic building a successful practice. Second, some nephrolo-
limitations of the test.13, 14 A medium-size 70-year-old gists may simply be too busy to provide care to patients
woman may have an SCr level of 1 mg/dL, a seeming- who are in the early stages of CKD. Indeed, a growing
ly normal level, despite a creatinine clearance (Ccr) as shortage of nephrologists may prompt PCPs, of
low as 40 mL/min, a rate that signals the presence of necessity, to focus increasingly on the care of patients
signiﬁcant kidney functional impairment. There with end-stage renal disease.15
appears to have been little educational effort to inform
PCPs about this pitfall of SCr levels. Moreover, the hec- Importance of communication
tic pace of primary care practice makes it unlikely that Many of the PCPs in our survey were disappointed
the PCP will have time to calculate an estimated Ccr. with the level of communication they typically
experience with nephrologists. Their complaints often patient aware of treatments that should have, but were
cited an inadequate explanation of tests that were not, previously provided.
ordered, and treatment and medication plans that were
prescribed. Consultation letters and phone calls to the Nephrologists, like any specialist, should take great
PCP can effectively address this type of complaint. care in their communication with referred patients not
to diminish the patient’s perception of their PCP. The
Written communication by the nephrologist to the nephrologist beneﬁts by clearly expressing both to the
PCP should be structured in a way that adequately PCP and the patient that the care they are providing is
informs the PCP of treatment plans and goals. The consultative, and that the nephrologist is working in
consultation note serves a broader purpose than simply collaboration with the PCP.
providing medical information; the letter builds on the
PCP’s perception of the nephrologist’s quality and com- Initiatives designed to inform PCPs of issues
pleteness of care. The letter also serves a marketing surrounding the care of CKD patients could go far
purpose, enhancing the PCP’s sense of the importance toward stimulating earlier referrals. In one interesting
and value of nephrology consultation. collegial approach, a nephrology group invited PCPs in
their geographic area to an evening session. A national
For patients with early CKD, the nephrologist should expert lectured on principles of CKD care. Participants
emphasize aspects of care that ought to be addressed, were then seated with ﬁve PCPs and a nephrologist at
including blood pressure management, identiﬁcation each table. Over dinner, the nephrologists led their PCP
and treatment of the CKD etiology, management of group through a structured discussion of CKD issues.
anemia and early bone disease, and the interaction The result was one of relationship building and an
between CKD and existing comorbidity. Similarly, enhanced and shared understanding of the respective
communication with the patient should reﬂect the roles the nephrologist and PCP play in the care of
value that the nephrologist’s involvement provides. patients with CKD.
Many PCPs fear “losing” patients to nephrologists.
Several issues likely stimulate this concern. The PCP
may have cared for the patient for many years, gaining Earlier referral of patients with CKD to nephrologists
the patient’s trust and cultivating a healthy therapeutic is an important goal to achieve if patient treatment is
relationship. Specialist referral may be viewed as dif- to improve. A variety of dynamic issues are involved
fusing the strength of this relationship. The PCP may in this process. Certain trends, such as the worsening
fear the loss of future income if the patient decides to shortage of nephrologists, may hinder efforts to
seek subsequent primary care from the nephrologist. increase the early referral of these patients. Strategies
Indeed, Campbell and colleagues16 found that 19% of such as the use of nurse practitioners and physician
surveyed PCPs expressed this concern. The PCP also assistants, and disease-management approaches,
may be worried that the nephrologist will make the offer promise. CKD
Table 2. Reasons Given by PCPs for Delaying Referral to Nephrologists*
Feel very capable of treating kidney-related problems 65% → 10%†
Have found little value in early nephrology consultation 80%
Fear of “losing” patient 34%
Financial referral issues 31%
Long delays to get appointments 25%
Old patients, comorbidity 20%
Fear of poor reﬂection on primary care 2%
51 of 105 PCPs surveyed delay referral until creatinine clearance is <50 mL/min.
65% initially reported that they felt capable of treating these patients: after being asked
to review their scores on the analog scale items, only 10% remained conﬁdent.
References 8. Sesso R, Belasco AG. Late diagnosis of chronic renal failure and
1. Jones CA, McQuillan GM, Kusek JW, et al. Serum creatinine levels mortality on maintenance dialysis. Nephrol Dial Transplant.
in the US population: Third National Health and Nutrition
Examination Survey (erratum in Am J Kidney Dis. 2000;35:178). 9. Jungers P, Zingraff J, Page B, Albouze G, Hannedouche T, Man NK.
Am J Kidney Dis. 1998;32:992-999. Detrimental effects of late referral in patients with chronic renal
failure: a case-control study. Kidney Int. 1993;41:S170-S173.
2. Obrador GT, Ruthazer R, Arora P, Kausz AT, Pereira BJ. Prevalence
of and factors associated with suboptimal care before initiation of 10. Eadington DW. Delayed referral for dialysis. Nephrol Dial
dialysis in the United States. J Am Soc Nephrol. 1999;10:1793-1800. Transplant. 1996;11:2124-2126.
3. Foley RN, Parfrey PS, Harnett JD, et al. Clinical and echocardio- 11. Schmidt RJ, Domico JR, Sorkin MI, Hobbs G. Early referral and its
graphic disease in patients starting end-stage renal disease therapy. impact on emergent ﬁrst dialyses, health care costs, and outcome.
Kidney Int. 1995;47:186-192. Am J Kidney Dis. 1998;32:278-283.
4. Levin A, Singer J, Thompson CR, Ross H, Lewis M. Prevalent 12. Franks P, Williams GC, Zwanziger J, Mooney C, Sorbero M. Why do
left ventricular hypertrophy in the predialysis population: physicians vary so widely in their referral rates? J Gen Intern Med.
identifying opportunities for intervention. Am J Kidney Dis. 2000;15:163-168.
1996;27:347-354. 13. Cockcroft DW, Gault MH. Prediction of creatinine clearance from
5. Kausz AT, Obrador GT, Pereira BJ. Anemia management in serum creatinine. Nephron. 1976;16:31-41.
patients with chronic renal insufﬁciency. Am J Kidney Dis. 14. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more
2000;36:S39-S51. accurate method to estimate glomerular ﬁltration rate from serum
creatinine: a new prediction equation. Modiﬁcation of Diet in Renal
6. McClellan WM, Knight DF, Karp H, Brown WW. Early
Disease Study Group. Ann Intern Med. 1999;130:461-470.
detection and treatment of renal disease in hospitalized diabetic
and hypertensive patients: important differences between practice 15. Bolton WK, Kliger AS. Chronic renal insufﬁciency: current under-
and published guidelines. Am J Kidney Dis. 1997;29:368-375. standings and their implications. Am J Kidney Dis. 2000;36:S4-S12.
7. Arora P, Obrador GT, Ruthazer R, et al. Prevalence, predictors, 16. Campbell JD, Ewigman B, Hosokawa M, Van Stone JC. The timing
and consequences of late nephrology referral at a tertiary care of referral of patients with end stage renal disease. Dial Transplant.
center. J Am Soc Nephrol. 1999;10:1281-1286. 1989;18:660-686.
Allen R. Nissenson, MD
Los Angeles, California
feature Brian J.G. Pereira, MD, MBA
Current care of patients with chronic kidney disease:
Opportunities for improvement
Better adherence to practices known to be of clinical beneﬁt not only will improve patient outcomes,
but also may reduce the cost of care.
Author information: Author information: Allen R. Nissenson, MD, is Professor of Medicine at the University of California, Los Angeles, and Director of the UCLA Dialysis Program.
Brian J.G. Pereira, MD, MBA, is Senior Vice President of the New England Medical Center, and Professor of Medicine at Tufts University School of Medicine
and the Sackler School of Graduate Biomedical Sciences. Dr. Nissenson is supported in part by the Richard Rosenthal Dialysis Fund.
ore than 6 million Americans have elevat- human erythropoietin (rHuEPO) was used infrequent-
ed serum creatinine (SCr) concentrations ly in 7.4% of patients. The majority of patients who
(≥ 1.5 mg/dL), and an estimated 2.5 mil- received rHuEPO exhibited moderate or severe
lion may have chronic kidney disease anemia, and very few patients with hematocrit (Hct)
(CKD) if CKD is deﬁned as SCr levels of 1.7 mg/dL or values of >32.9% received this medication.7 For the
greater.1 Unfortunately, a number of studies have most part, the patients who received rHuEPO also
revealed that patients with CKD are not routinely being exhibited the most severe CKD on the basis of SCr val-
identiﬁed in the early stages of their disease.2-5 In addi- ues. In addition, at any given Hct level, the likelihood
tion, even after they have been diagnosed, many CKD that a patient would be treated with rHuEPO increased
patients may not be receiving optimal treatment based with increasing SCr values. Finally, it was uncommon
on current standards of care.2, 5, 6 for patients to receive rHuEPO unless patients had
been seen by a nephrologist, even after controlling for
This may prove to be penny wise and pound foolish
CKD severity and Hct level. More detailed analyses of
in the long term. Early identiﬁcation and comprehen-
anemia and its treatment in this cohort are ongoing.
sive treatment of these patients may have a signiﬁcant
impact not only on their quality of life, but also on the
overall cost of their care. The following steps are crucial:
ACE inhibitor use
As shown in a recent meta-analysis,8 angiotensin-
Timely introduction of therapies to slow the converting enzyme (ACE) inhibitor use among patients
progression of CKD with CKD is effective in slowing the progression of
Identiﬁcation and management of the comorbidi- renal disease, whether or not the patient also suffers
ties commonly associated with CKD (eg, diabetes from diabetes mellitus (DM). A recent analysis by
mellitus and heart disease) Golan and colleagues9 demonstrated that the use of
ACE inhibitor therapy for patients with type 2 DM is
Management of common complications of CKD also cost-effective. There were several noteworthy
(eg, anemia and renal osteodystrophy) ﬁndings regarding the use of ACE inhibitors in our
Smooth transitions to renal replacement therapy cohort7 (see Table 1):
Use of ACE inhibitors among patients with CKD
We recently conducted a study of the patterns of was disappointingly low, particularly among
practice for the treatment of 1,658 patients with CKD patients with SCr values of ≥ 4 mg/dL. During the
at a large, integrated health maintenance organization ﬁrst year after entry into the study, fewer than
(HMO) in New Mexico.7 Because an extensive database, half of the patients with CKD had been prescribed
with considerable patient-speciﬁc information, was an ACE inhibitor.
available for analysis, we were able to gain insights into
the health care resources used by patients with CKD, When SCr values were ≤ 3.9 mg/dL, the percent-
including their patterns of hospitalization, use of vari- age of patients who received an ACE inhibitor
ous types of outpatient providers, and use of outpatient was similar regardless of SCr level, but
prescription medications. These observations have this percentage decreased to less than 20% when
added new information to our understanding of how SCr levels were ≥ 4 mg/dL.
patients with CKD are being treated. Although the likelihood of ACE inhibitor use was
higher among diabetic patients with CKD than
Erythropoietin use among nondiabetic patients with CKD, ACE
Although the prevalence of anemia was high among inhibitor use among diabetic patients was still
the patients with CKD in our cohort, recombinant low, regardless of their SCr values, ranging from
Table 1. Percentage of Patients Who Received an ACE Inhibitor, According to SCr Category
and Whether They Were Seen by a Nephrologist
SCr Category All Patients Patients Seen by Nephrologist* Patients Not Seen by
All patients n=1,658 n=317 n=1,341
All (n=1,658) 0.34 0.31 0.35
<2.0 mg/dL (n=1,203) 0.36 0.38 0.36
2.0 to 2.9 mg/dL (n=289) 0.31 0.31 0.31
3.0 to 3.9 mg/dL (n=53) 0.43 0.42 0.45
≥4.0 mg/dL (n=113) 0.15 0.16 0.09
Diabetic patients n=425 n=109 n=316
All (n=425) 0.49 0.44 0.51
<2.0 mg/dL (n=287) 0.50 0.56 0.50
2.0 to 2.9 mg/dL (n=75) 0.59 0.57 0.60
3.0 to 3.9 mg/dL (n=20) 0.45 0.43 0.56
≥4.0 mg/dL (n=43) 0.28 0.28 0.29
Nondiabetic patients n=1,233 n=208 n=1,025
All (n=1,233) 0.29 0.24 0.30
<2.0 mg/dL (n=916) 0.32 0.32 0.32
2.0 to 2.9 mg/dL (n=214) 0.21 0.19 0.22
3.0 to 3.9 mg/dL (n=33) 0.41 0.41 0.41
≥4.0 mg/dL (n=70) 0.05 0.05 0.06
Seen by a nephrologist within 1 year after entry into the CKD cohort.
45% to 59% for SCr values below 4.0 mg/dL, ment of these associated comorbid conditions can
down to 28% for SCr values of 4.0 mg/dL and reduce hospitalizations for these patients. Cardio-
above. vascular disease is highly prevalent among patients
with CKD and often leads to hospitalization.14, 15 Closer
Perhaps even more disappointing was the
attention to the management of heart disease in this
observation that the likelihood of ACE inhibitor
population, as outlined by Meyer and Levey in a
use was no higher among patients with CKD National Kidney Foundation report,16, 17 could substan-
who were cared for by a nephrologist than by tially improve outcomes. In addition, several studies
a primary care physician (PCP), even after demonstrated that even partial correction of anemia
controlling for CKD severity. with rHuEPO (to a hemoglobin level of 11 to 12 g/dL)
Although previous reports10—13 documented the among dialysis patients may prevent left ventricular
effects of late referral of patients with CKD to nephrol- hypertrophy from developing or may lead to its
ogists, this study provides a more complete view of the regression.18, 19
current practice patterns for these patients, including
In 1994, a National Institutes of Health Consensus
a number of aspects of care not previously well
Development Conference on CKD20 recommended that
a nephrologist be consulted early in the course of renal
disease (when SCr values reach 1.5 mg/dL for women
Comorbid conditions or 2 mg/dL for men) so that appropriate diagnostic
Patients with CKD often suffer from other serious tests can be performed and interventions, when avail-
conditions as well. Careful attention to the manage- able, can be prescribed.
Table 2. Percentage of Patients Who Visited a PCP or Nephrologist, According to SCr Category
SCr Category Annualized Percentage
All (n=1,658) 0.88 0.22
<2.0 mg/dL (n=1,203) 0.93 0.12
2.0 to 2.9 mg/dL (n=289) 0.86 0.31
3.0 to 3.9 mg/dL (n=53) 0.82 0.72
≥4.0 mg/dL (n=113) 0.50 0.80
PCP = primary care physician
The type of provider was assessed on the basis of specialty-speciﬁc location-of-service codes used by the health maintenance organization.
In our study,7 however, only a minority of patients late are more likely to present for dialysis with pul-
with CKD were seen by a nephrologist during the ﬁrst monary edema, the need for temporary vascular
year of observation after entry into the study (Table 2). access, hypoalbuminemia, severe uremia,10 and meta-
Although the percentage of patients who visited a bolic acidosis.12 Late referrals of patients to nephrologist
nephrologist during the ﬁrst year of the study further increase the need for invasive therapeutic
increased with increasing SCr values, nephrologists measures, clinical morbidity, and, ultimately, costly
tended not to be involved in the care of patients whose hospitalization.12 Several studies have demonstrated
SCr values were lower than 3 mg/dL. that late referral increases morbidity and costs for
patients with CKD.10-13
Unfortunately, the experience we observed is typical
of clinical practice throughout the United States. Even when patients are referred to a nephrologist,
Among another cohort of patients who were over the some aspects of care that have proven beneﬁcial for
age of 65 before the initiation of dialysis, 81% had not patients with CKD are not adhered to consistently.
been seen by a nephrologist until 3 months before For example, there was no evidence in our study that
beginning dialysis, and 47% had not been seen by a patients with CKD who visited a nephrologist had a
nephrologist until 1 month before dialysis.2 Two other higher likelihood of ACE inhibitor use than did those
ﬁndings from our study7 are worth noting: Diabetes who did not visit a nephrologist.7 In addition, signiﬁ-
mellitus, hypertension, or both were signiﬁcantly cant numbers of anemic patients with CKD who
associated with increased SCr and were increasingly visited a nephrologist did not receive rHuEPO. Our
prevalent with higher SCr values. In addition, the ﬁndings are consistent with practices observed
number of hospitalizations increased directly with the in other settings.10, 21
level of SCr (Table 3), and the majority of hospital-
izations were related to associated comorbidities, Although in some cases this may reﬂect inadequate
rather than to CKD itself. resources to pay for this costly medication, this is not
the explanation for many patients. Rather, the physi-
Discussion cian, whether a PCP or a nephrologist, has simply not
The consequences of these late referrals to a treated the anemia. Similarly, McClellan and col-
nephrologist are devastating. Patients who are referred leagues21 demonstrated that ACE inhibitors are infre-
Table 3. Hospital Utilization by Patients With CKD
SCr Category Hospitalization Utilization
All (n=1,658) 0.84
<2.0 mg/dL (n=1,203) 0.72
2.0 to 2.9 mg/dL (n=289) 0.96
3.0 to 3.9 mg/dL (n=53) 1.20
≥4.0 mg/dL (n=113) 1.56
quently prescribed for patients with CKD who are 8. Kshirsagar AV, Joy MS, Hogan SL, Falk RJ, Colindres RE. Effect of
ACE inhibitors in diabetic and nondiabetic chronic renal disease: a
being discharged from the hospital. The appropriate systematic overview of randomized placebo-controlled trials. Am J
use of rHuEPO and ACE inhibitors could substantially Kidney Dis. 2000;35:695-707.
improve outcomes for this patient population. 9. Golan L, Birkmeyer JD, Welch HG. The cost-effectiveness of treat-
ing all patients with type 2 diabetes with angiotensin-converting
enzyme inhibitors. Ann Intern Med. 1999;131:660-667.
For monitoring of nutritional status, effects of
reduced-protein diets, use of appropriate multivita- 10. Arora P, Obrador GT, Ruthazer R, et al. Prevalence, predictors, and
consequences of late nephrology referral at a tertiary care center.
mins, and control of phosphorus and sodium intake, J Am Soc Nephrol. 1999;10:1281-1286.
the routine availability of a trained dietitian is essential 11. Sesso R, Belasco AG. Late diagnosis of chronic renal failure and
for the optimal treatment of patients with CKD. mortality on maintenance dialysis. Nephrol Dial Transplant.
The results of our study suggest numerous opportu- 12. Jungers P, Zingraff J, Page B, Albouze G, Hannedouche T, Man NK.
Detrimental effects of late referral in patients with chronic renal
nities to improve outcomes for this patient population. failure: a case-control study. Kidney Int. 1993;41:S170-S173.
Better adherence to practices known to be of clinical
13. Schmidt RJ, Domico JR, Sorkin MI, Hobbs G. Early referral and its
beneﬁt not only will improve patient outcomes but also impact on emergent ﬁrst dialyses, health care costs, and outcome.
may reduce the cost of care. Because of the high clini- Am J Kidney Dis. 1998;32:278-283.
cal and ﬁnancial costs of ESRD programs, providers 14. Xia H, Ebben J, Ma JZ, Collins AJ. Hematocrit levels and hospital-
and policy-makers should view CKD as a major public ization risks in hemodialysis patients. J Am Soc Nephrol. 1999;10:
health problem and should initiate innovative pro-
grams to address this growing patient population. CKD 15. Collins AJ, Li S, St Peter W, et al. Death, hospitalization, and eco-
nomic associations among incident hemodialysis patients with
hematocrit values of 36 to 39%. J Am Soc Nephrol. 2001;12:2465-
References 16. Meyer KB, Levey AS. Controlling the epidemic of cardiovascular
1. Jones CA, McQuillan GM, Kusek JW, et al. Serum creatinine levels disease in chronic renal disease: report from the National Kidney
in the US population: Third National Health and Nutrition Foundation Task Force on cardiovascular disease. J Am Soc
Examination Survey. Am J Kidney Dis. 1998;32:992-999 (erratum Nephrol. 1998;9(suppl 12):S31-S42.
in Am J Kidney Dis. 2000;35:178)
17. Levey AS, Beto JA, Coronado BE, et al. Controlling the epidemic of
2. Obrador GT, Pereira BJ. Early referral to the nephrologist and timely cardiovascular disease in chronic renal disease: What do we know?
initiation of renal replacement therapy:a paradigm shift in the man- What do we need to learn? Where do we go from here? National
agement of patients with chronic renal failure. Am J Kidney Dis. Kidney Foundation Task Force on Cardiovascular Disease. Am J
1998;31:398-417. Kidney Dis. 1998;32:853-906.
3. Eadington DW. Delayed referral for dialysis. Nephrol Dial 18. Macdougall IC, Lewis NP, Saunders MJ, et al. Long-term cardiores-
Transplant. 1996;11:2124-2126. piratory effects of amelioration of renal anaemia by erythropoietin.
4. Levin A. Anaemia in the patient with renal insufﬁciency: docu-
menting the impact and reviewing treatment strategies. Nephrol 19. Martinez-Vea A, Bardaji A, Garcia C, Ridao C, Richart C, Oliver JA.
Dial Transplant. 1999;14:292-295. Long-term myocardial effects of correction of anemia with recom-
binant human erythropoietin in aged patients on hemodialysis.
5. Jungers P. Screening for renal insufﬁciency: Is it worth while? Is it Am J Kidney Dis. 1992;19:353-357.
feasible? Nephrol Dial Transplant. 1999;14:2082-2084.
20. National Institutes of Health Consensus Development Conference
6. Obrador GT, Ruthazer R, Arora P, Kausz AT, Pereira BJ. Prevalence Panel N. Morbidity and mortality of renal dialysis: an NIH
of and factors associated with suboptimal care before initiation of consensus conference statement. Consensus Development
dialysis in the United States. J Am Soc Nephrol. 1999;10:1793-1800. Conference Panel. Ann Intern Med. 1994;121:62-70.
7. Nissenson AR, Collins AJ, Hurley J, Petersen H, Pereira BJ, 21. McClellan WM, Knight DF, Karp H, Brown WW. Early detection
Steinberg EP. Opportunities for improving the care of patients with and treatment of renal disease in hospitalized diabetic and hyper-
chronic renal insufﬁciency: current practice patterns. J Am Soc tensive patients: important differences between practice and pub-
Nephrol. 2001;12:1713-1720. lished guidelines. Am J Kidney Dis. 1997;29:368-375.
One-on-One Gerald Bernstein, MD
New York, New York
Care of the diabetic nephropathy patient: a team
effort toward optimal outcomes
A large percentage of people with chronic kidney disease is diabetic. Their optimal treatment
will require overcoming current gaps in medical education.
Of US patients who reach end-stage renal disease (ESRD), (ESRD) had a permanent vascular
more than 40% do so because of diabetic nephropathy.1 As access before starting dialysis, and
the diabetes in most of these patients is already being treat-
almost one third were still using
ed, endocrinologists are in a position to diagnose chronic
kidney disease (CKD) in its early stages, before it has
temporary access 30 days after dialysis
progressed to ESRD. initiation. Too many of these patients
also seemed to have albumin, serum
Blood pressure control, optimization of angiotensin-convert- creatinine (SCr), and hemoglobin (Hb)
ing enzyme inhibitor therapy, anemia treatment, treatment of levels that, in an ideal world, would
bone disease, attention to nutrition, selection of renal replace- have been better controlled. Why
ment modality in late-stage disease, and vascular access
don’t people get better care prior
planning all are important aspects of care in all CKD
patients. Data from the US Renal Data System (USRDS),
however, reveal notable deﬁciencies in such care. In a recent
GERALD BERNSTEIN, MD: I think it goes back
study2,3 utilizing USRDS data, Obrador and colleagues found
to what we were taught—that once the process of
that 60% of patients had albumin concentrations below the
kidney failure starts, it's inexorable and will progress.
lower limit of normal when they began dialysis. According
Although chronic kidney disease (CKD) cannot be
to another study,1,4 only 44% of patients had a functioning
prevented from progressing, you can slow the process
permanent vascular access before starting dialysis, and 27%
dramatically with such things as angiotensin-convert-
were still using a temporary access 30 days after dialysis initi-
ing enzyme (ACE) inhibitors, a proper diet, blood
ation. These ﬁgures indicate that patients have not had well-
coordinated care in the time leading up to dialysis. This is true pressure management, management of diabetes, etc.
of both diabetic and nondiabetic patients. The opportunity to These aspects of care for patients with CKD are
improve care is particularly feasible in diabetics, however, probably not emphasized enough in general medicine.
since they are often being followed by primary care physicians
CKD: Do comfort levels have anything to do
(PCPs) or endocrinologists when kidney disease ﬁrst begins.
with it? It’s rational to speculate, for
CKD induces ﬁrst mild and then severe anemia, regardless instance, that PCPs are comfortable
of the primary cause of kidney functional loss. In diabetic treating hypertension and prescribing
nephropathy, the onset of anemia caused by erythropoietin ACE inhibitors. It’s less likely they
deﬁciency can occur early, well before ESRD.5 Recent would be comfortable treating CKD-
experience with the “glitazones” (thiazolidinediones) has raised
related anemia or bone and mineral
the awareness of anemia among endocrinologists; still, only
metabolic disorders, or providing
about 20% of patients who begin dialysis with a hematocrit
(Hct) level of 30% or less have received recombinant human nutrition and dialysis education.
erythropoietin (rHuEPO) before reaching ESRD.3
BERNSTEIN: Even if they have some degree of
CKD—THE JOURNAL OF CHRONIC KIDNEY DISEASE comfort, they may not be treating aggressively enough
interviewed Gerald Bernstein, MD, on issues surrounding compared with someone who provides those services
the care and referral of patients with diabetic nephropathy. all the time in order to reach certain targets.
A former president of the American Diabetes Association,
CKD: According to a study by Obrador and
Bernstein is currently an attending physician at Beth Israel
Medical Center in New York.
colleagues,3 80% of patients initiating
dialysis with hematocrit (Hct) levels
CKD: According to US Renal Data System less than 28% had not received treat-
(USRDS) data,1 less than half of ment with rHuEPO. Does that ﬁnding
patients with end-stage renal disease surprise you?
BERNSTEIN: No, it doesn’t surprise me. As a family because of a drop in Hb level, nor do I know many
practitioner or internist, you learn certain things about physicians who have.
the natural history of kidney disease. The understand-
ing is that it is natural for someone whose SCr level CKD: Did you ever take any steps to
begins to rise to have a fall in Hct level. And when treat anemia?
that happens, the individual compensates through
biochemical mechanisms to deliver more oxygen to
BERNSTEIN: No, because it was regarded as natural
the tissues. For most physicians, that’s where it leaves
off. It certainly did with me. CKD: In the past several years, in your
The typical approach for most physicians—if the opinion, has the awareness of anemia
Gerald Bernstein, MD patient’s guaiac test is negative and bleeding can be increased, decreased, or remained
is a former president ruled out—is simply to observe the patient. If the SCr the same?
of the American level is 2.5 mg/dL, that’s no big issue because the
Diabetes Association. patient is not ready for dialysis. Why do I need to BERNSTEIN: For the most part, I think it has
He is currently an make a referral if the patient has no speciﬁc signs or remained the same. The sophisticated medical commu-
attending physician at symptoms related to SCr level? nity is giving it more attention, but I don’t think that’s
Beth Israel Medical
the case in the general medical community.
Center in New York. CKD: Somewhere along the line it appears
CKD: According to a consensus statement
you developed a different view of this
from the National Institutes of Health,6
scenario. When did that happen?
referral to a nephrologist for CKD is
BERNSTEIN: A number of years ago. Having a large recommended at SCr levels of 1.5
diabetes practice, I’ve been very much involved with and 2.0 mg/dL for women and men,
nephrologists. We’ve had many patients who have pro- respectively. Do you agree that people
gressed to dialysis over 20 or 30 years, so I was no with this level of kidney functional
stranger to dialysis and the issues of vascular access. impairment should be referred
For us the question was, when do we refer? For the to a nephrologist?
most part, we didn’t refer to nephrologists until SCr
BERNSTEIN: Most nephrologists probably would not
was up around 5 mg/dL. If the Hb level dropped to
incorporate those people into a major part of their pro-
8 g/dL, well, we were not alarmed because that’s what
gram. As I mentioned, I referred patients relatively
we were taught happens to these people. If they’re
early—when SCr levels were no higher than 3 mg/dL.
functioning and going to work and don’t feel badly,
I’ve worked with some well-respected nephrologists,
and they’re not unusually acidotic or have a variety of
and none has ever suggested that I should be referring
other clinical issues, then there’s no need to make a
earlier. And these were nephrologists with whom our
referral. When their SCr level got to around 5 mg/dL,
communications were very strong; it’s not as though
we ﬁgured that even in the best of situations it might
they were afraid of insulting me.
be another year or so before they would need dialysis.
We then would make the referral for the access—and CKD: Based on the National Kidney
this was usually before even the nephrologist was Foundation Kidney Disease Outcomes
ready to address the access.
Quality Initiative (NKF K/DOQI) guide-
What began to become apparent as I watched lines, however, they probably should
nephrologists was that nephrologists were much more be urging earlier referral. Perhaps
focused on achieving certain goals, and the goals were more educational efforts are
beyond what I could have achieved. My ofﬁce wasn’t needed in nephrology?
set up to accomplish these goals, nor was I attuned to
the needs of the patient in the same preventative way BERNSTEIN: I think the problem has to be docu-
during the early stages kidney of disease evident by mented and sold more aggressively. There are many
rising SCr levels. medical conditions that were not treated in the past
because the treatments were not available, or at least
A number of years ago, I began to change my prac- not generally available. The more medical care
tices and started making referrals when SCr levels were advances, the more tools that you have and the more
between 2.5 and 3 mg/dL. I never made a referral problems become treatable at an earlier stage.
That’s where we are now with anemia; it is becom- BERNSTEIN: I’m sure that’s a factor. Subclinical
ing more widely recognized that earlier treatment of adverse effects are also a major part of diabetes care.
anemia may make a clinical difference in a patient’s Even a slight elevation in blood glucose will act as a
life. In diabetes, we’re always dealing with quality-of- poison over a period of 10 or 20 years and lead to
life (QOL) issues and the aggressive need to control kidney disease. Yet patients may not have any symp-
blood sugar. There are good data7 showing that blood toms—or think they don’t have any symptoms.
sugar control is associated with signiﬁcant QOL Then it depends on the degree of pursuit.
improvements. But a lot of people don’t know that
their QOL is not so great because nobody asks them, One area that is a bit similar is diabetic stomach
and they assume everybody feels the way they feel. disease. These people often are symptomatic, but their
symptoms fall within a range of minor complaints that
CKD: The use of Hct and SCr measurements seem normal. Patients say, “Well, I've got an upset
is in question. The recent NKF-K/DOQI stomach, I’ve got a little reﬂux, I feel bloated,” that
guidelines8 suggest that Hb should be kind of thing. They might talk to someone who doesn’t
used instead of Hct as a quantiﬁer of have diabetes who has the same complaints. It doesn’t
anemia in CKD patients. Additionally, appear to the patient to be an issue until it reaches
it’s recognized that SCr levels underes- an advanced stage.
timate kidney functional impairment in
CKD: What do we know about diabetes
many patients9; consequently, there
control and its effect on CKD?
appears to be increasing support for
the routine use of formulas that esti- BERNSTEIN: We know that controlling both blood
mate glomerular ﬁltration rate (GFR).10, 11 glucose and blood pressure can slow the progression of
Are these messages being conveyed CKD.12 There’s some interesting unpublished data indi-
to the general practitioner and cating that people with even advanced kidney disease
endocrinologist? may, if they live long enough, demonstrate reversal
of some of their kidney disease if their diabetes is
BERNSTEIN: Not really. I read at least three general extremely well controlled in that interval.
medical journals, and these issues are almost never
discussed. A recent study by Bosman and colleagues5 showed
that people with diabetes develop anemia earlier than
Most of us some time ago learned that there was a people without diabetes, given the same SCr levels.
straight-line relationship between SCr and GFR. Again, That’s an important observation that I’d like to see
in the more sophisticated metabolic community, we’ve corroborated.
begun to understand that such a straight-line relation-
ship does not always hold true. But in the general med- CKD: You seem to have developed a good
ical community, no, this is not widely appreciated. relationship with nephrologists. But
Most physicians don’t have the opportunity to interact you also have been in a position to
with “superspecialists” to get this kind of information. know what others have experienced
I would suspect if you looked at a series of grand
in caring for their patients with dia-
rounds held over the course of the last year or two,
there would be little or no discussion of this.
betic nephropathy. Are there some
general lessons that you’ve learned
CKD: There’s also growing evidence of in terms of referral to and interaction
adverse effects associated with Hb with nephrologists?
levels less than 10 g/dL in people with
CKD even prior to ESRD.3, 8 Is it fair to BERNSTEIN: It’s important to remember that the
nephrologist has a team. The nephrologist works with a
say that this information also is not
nutritionist the same way the endocrinologist works
with a nutritionist. The practicing physician needs to
BERNSTEIN: Yes, that’s fair to say. delegate more of the responsibility for certain elements
of the care of patients to nonphysicians—the diabetes
CKD: Many of these adverse effects are educator and the kidney educator—who then can
subclinical. Is that why anemia is not spend the appropriate amount of time sorting out what
being picked up earlier? needs to be done and getting the patient on the right
path. The physician simply doesn’t have time to do 5. Bosman DR, Winkler AS, Marsden JT, et al. Anemia with erythropoi-
etin deﬁciency occurs early in diabetic nephropathy. Diabetes Care.
this in the ordinary working day. 2001;24:495-499.
The earlier the intervention, the better. We need 6. National Institutes of Health. Morbidity and mortality of dialysis: an
aggressive nephrologists who will bring in patients NIH consensus statement. NIH Consensus Statement. United States:
National Institutes of Health; 1993:1-33.
even if the patients don’t need to be seen often, and
who will get patients involved with the education 7. Testa MA, Simonson DC. Health economic beneﬁts and quality of
life during improved glycemic control in patients with type 2 dia-
process. The nephrology educator can then monitor betes mellitus: a randomized, controlled, double-blind trial. JAMA.
them for such developments as diminished Hb level 1998;280:1490-1496.
or a slow increase in SCr level, and alert the nephr- 8. National Kidney Foundation. NKF-K/DOQI Clinical Practice
ologist as to when patients need additional medical Guidelines for Anemia of Chronic Kidney Disease: update 2000.
treatment. CKD Am J Kidney Dis. 2001;37(suppl 1):S182-S238.
9. Jones CA, McQuillan GM, Kusek JW, et al. Serum creatinine levels
References in the US population: Third National Health and Nutrition
Examination Survey. (erratum in Am J Kidney Dis. 2000;35:178)
1. US Renal Data System. USRDS 1999 annual data report. Bethesda,
Am J Kidney Dis. 1998;32:992-999.
Md: National Institute of Diabetes and Digestive and Kidney
Diseases, National Institutes of Health; 1999.
10. Cockcroft DW, Gault MH. Prediction of creatinine clearance from
2. US Renal Data System. USRDS 1996 annual data report. Bethesda, serum creatinine. Nephron. 1976;16:31-41.
Md: National Institutes of Health, National Institutes of Diabetes and
11. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more
Digestive and Kidney Disease; 1996.
accurate method to estimate glomerular ﬁltration rate from serum
3. Obrador GT, Ruthazer R, Arora P, Kausz AT, Pereira BJ. Prevalence of creatinine: a new prediction equation. Modiﬁcation of Diet in Renal
and factors associated with suboptimal care before initiation of dialy- Disease Study Group. Ann Intern Med. 1999;130:461-470.
sis in the United States. J Am Soc Nephrol. 1999;10:1793-1800.
12. Zabetakis PM, Nissenson AR. Complications of chronic renal
4. National Institute of Diabetes and Digestive and Kidney Diseases. insufﬁciency: beyond cardiovascular disease. Am J Kidney Dis.
Healthy People 2010: Chronic Kidney Disease. 2000. 2000;36:S31-S38.
feature By Eli A. Friedman, MD
Brooklyn, New York
Perspectives on diabetic nephropathy
Author information: Eli A. Friedman, MD, is Distinguished Teaching Professor of Medicine and Chief of the Renal Disease Division, Department of Medicine, State University
of New York Health Science Center at Brooklyn, NY. He is a recipient of both the American Association of Kidney Patients Medal of Excellence and the
American Kidney Fund’s National Torchbearer Award.
Diabetic nephropathy is the leading cause of end-stage on this understanding, may soon make the task of car-
renal disease (ESRD). Clinicians and researchers are opti- ing for diabetic patients with major complications far
mistic, however, that new therapies may make diabetes less daunting. The hope is that, within the very near
more manageable and limit its impact on the kidneys. future, the prognosis for diabetic vasculopathy and
nephropathy will be transformed from hopeless, inex-
orable deterioration to a manageable metabolic disor-
ccording to the World Health
der permitting full function and even cure.
Organization, type 2 diabetes mellitus
may afﬂict 300 million individuals world- This article discusses the options available to the dia-
wide by 2025.1 In the United States, betic ESRD patient and the need for overall diabetic
according to the National Institutes of Health’s National care during uremia therapy.
Diabetes Information Clearinghouse, 15.7 million peo-
ple—almost 6% of the population—have diabetes.2 One Options for ESRD treatment in diabetes
third of these people are unaware of their disorder.
Diabetic ESRD patients are managed similarly to
Diabetes was the seventh leading cause of death listed
nondiabetic ESRD patients with two exceptions: First,
on US death certiﬁcates in 1996, contributing to
simultaneous pancreas and kidney transplantation
193,140 deaths. More than 798,000 new cases are diag-
is a diabetes-speciﬁc therapy. Second, in our experi-
nosed each year. Health care expenditures for diabetes-
ence, diabetic patients are more likely than nondiabetic
related problems amount to a minimum of $98 billion
patients to decline treatment, an option we refer to as
annually in the United States, and may be even higher.2
Diabetic nephropathy is the leading cause of end- ESRD in diabetic persons reﬂects the demographics
stage renal disease (ESRD) in the United States, Japan, of diabetes per se in that the incidence is higher in
and most of industrialized Europe.3 As noted in the US African Americans, Hispanics, and Native Americans,3,
Renal Data System (USRDS) 2001 annual report, more 4, 8
and the peak incidence of ESRD occurs from the 5th
than 40% of all ESRD patients had diabetes at initiation to the 7th decade.8, 9 Blacks older than age 65 years face
of therapy.4 Although much attention has been given to a 7-fold greater risk of diabetes-related kidney failure
kidney disease in type 1 diabetes, the prevalence of than do whites.8
kidney disease caused by type 2 diabetes is signiﬁcant.3
Contrary to widely prevalent thinking, kidney disease Type 2 diabetes accounts for the majority of patients
is as likely to develop in type 2 diabetes as in type 1.5 who require renal replacement therapy (RRT)4; how-
While there are differences in the prevalence of diabetic ever, there is often confusion over diabetes type.10
nephropathy among racial and ethnic groups,3 other Consequently, literature reports of the outcome of
aspects of the two disorders—particularly the progres- ESRD therapy by diabetes type are few and imprecise.
sion of nephropathy—are remarkably similar.6 Vasculopathic complications of diabetes, such as hyper-
tension, have approximately the same impact on the
Diabetic patients with kidney disease have the worst progression of diabetic nephropathy in type 2 diabetes
overall age-adjusted survival rate of all patients with as in type 1 diabetes.6
ESRD.4 When compared to patients with other causes
of ESRD, diabetic patients have greater mortality and Depending on age, severity of comorbid disorders,
morbidity due to comorbid disorders, especially cardio- available local resources, and patient preference, the
vascular and cerebrovascular disease.7 Given these uremic diabetic patient may be managed according
facts, the prognosis for patients with kidney disease to different protocols (Table 1). Unfortunately, in the
and diabetes seems uniformly grim. However, there is so-called preterminal care of diabetic patients with
cause for considerable optimism. Continuing advances ESRD, inadequate attention often is paid to the control
in understanding the pathogenesis of diabetic kidney of hypertension, hyperlipidemia, anemia, and
disease, and the development of new therapies based ophthalmologic problems.
Table 1. Options in Uremia Therapy for ment regimen that will be employed.11 Approximately
Diabetic ESRD Patients 12% of diabetic persons with ESRD will be treated by
peritoneal dialysis (PD), while the remaining 8% will
1. No speciﬁc uremia intervention
(passive suicide) receive a kidney transplant.11
2. Peritoneal dialysis Rehabilitation is difﬁcult in diabetic ESRD patients.
Intermittent peritoneal dialysis We have found that a couple of factors are especially
Continuous ambulatory important. First, patients tend to fare best when they
peritoneal dialysis participate in the design of their own treatment regi-
Continuous cyclic peritoneal dialysis men. Second, a functioning kidney transplant permits
markedly superior rehabilitation than that attained
by either HD or PD.
Home hemodialysis Hemodialysis
4. Kidney transplantation We have found that as many as 55% of diabetic HD
Cadaver donor kidney patients were unable to perform routine living chores
without assistance vs 25% of nondiabetic HD patients.12
Living donor kidney
In one study of 430 patients, the percentage of individ-
5. Pancreas plus kidney transplantation uals requiring a wheelchair was almost 3-fold higher in
diabetic vs nondiabetic patients: 29% vs 10%.12 Other
studies have conﬁrmed these observations.11 The
For the large majority—more than 80% of diabetic inescapable conclusion of studies to date is that main-
persons who develop ESRD in the United States—main- tenance HD does not permit a full return to life's
tenance hemodialysis (HD) is the only renal replace- responsibilities for most diabetic individuals.
Survival of Diabetic ESRD Patients
Percent Surviving Live Donor
80 75.4% Transplant
61.6% 71.0% Dialysis
0 1 2 5 10
USRDS 2000 Years After Initiating Treatment
Figure 1: Long-term survival of diabetic ESRD patients shows the grim chances of surviving for a decade on dialysis (data for HD
and PD are pooled). Fewer than 1 in 25 diabetic patients treated by dialysis will live for 10 years.9
Table 2. Comparison of ESRD Options for Diabetic Patients
Factor Peritoneal Dialysis Hemodialysis Kidney Transplant
Extensive extrarenal No limitation No limitation except Excluded in cardiovascular
disease for hypotension insufﬁciency
Geriatric patients No limitation No limitation Arbitrary exclusion as
determined by program
Complete Rare, if ever Very few individuals Common as long
rehabilitation as graft functions
Death rate Much higher than Much higher than About the same as
for nondiabetics for nondiabetics for nondiabetics
First-year survival About 75% About 75% >90%
Survival to second Almost never Fewer than 5% About 1 in 5
Progression of Usual and unremitting. Usual and unremitting. Interdicted by functioning
complications Hyperglycemia and May beneﬁt from pancreas and kidney. Partially
hyperlipidemia metabolic control. ameliorated by correction of
Disadvantages Peritonitis, Blood access a hazard Cosmetic disﬁgurement,
hyperinsulinemia, for clotting, hemorrhage, hypertension, personal expense
hyperglycemia, and infection. Cyclical for cytotoxic drugs. Induced
hyperlipidemia. Long hypotension, weakness. malignancy. Human
hours of treatment. More Aluminum toxicity, immunodeﬁciency virus
days hospitalized than amyloidosis. transmission.
either hemodialysis or
Patient acceptance Variable, usually Variable, often Enthusiastic during periods of
compliant with passive noncompliant with good renal allograft function.
tolerance for regimen. dietary, metabolic, or Exalted when pancreas
antihypertensive proffers euglycemia.
component of regimen.
Bias in comparison Delivered as ﬁrst choice Treatment by default. All kidney transplant programs
by enthusiasts, although Often complicated by preselect those patients with
emerging evidence inattention to fewest complications.
indicates substantially progressive cardiac and Exclusion of older patients
higher mortality than peripheral vascular obviously favorably
for hemodialysis. disease. prejudices outcome.
Relative cost Most expensive over Less expensive than Pancreas/kidney engraftment
long run. kidney transplant in ﬁrst most expensive uremia therapy
year, subsequent years for diabetic. After ﬁrst year,
more expensive. kidney transplant alone is
(From Friedman,11 1999).
Peritoneal dialysis Evaluating the option of a combined pancreas and
kidney transplant for the diabetic ESRD patient is difﬁ-
In the United States, about 7% of diabetic ESRD
cult. Although still regarded as investigational by some,
patients are sustained by a form of PD, continuous
pancreas transplantation is growing in acceptability
ambulatory peritoneal dialysis (CAPD).9 The advan-
and technical success.14, 15 A recent American Diabetes
tages of this form, include freedom from a machine,
Association position statement recommends that sim-
ability to perform the procedure at home, rapid train- ultaneous pancreas-kidney (SPK) and pancreas-after-
ing, minimal cardiovascular stress, and avoidance of kidney transplantation should be routine in diabetic
heparin.11 Mechanical cycling of dialysate, termed con- kidney transplant recipients.15
tinuous cyclic peritoneal dialysis, can be performed
during sleep.11 Some clinicians characterize CAPD as a Comorbid risk factors
“ﬁrst-choice treatment” for diabetic ESRD patients. Management of diabetic patients with progressive
chronic kidney disease (CKD) is more difﬁcult than in
Not all reports on CAPD are positive, however. Rubin
age- and gender-matched nondiabetic patients.
and Hsu13 offered a less-enthusiastic assessment of
Treatment is often complicated by comorbid conditions
CAPD in diabetic patients based on experience in a
affecting other organ systems, including the eyes
largely African American diabetic population in
(retinopathy), heart (cardiovascular disease), and
Jackson, Miss. Only 34% of patients remained on
nervous system (peripheral or autonomic neuropathy).
CAPD after 2 years, and at 3 years, only 18%
Associated clinical syndromes must be followed and
continued on CAPD. treated, if possible, while preparing the patient to
A decision to select CAPD must therefore weigh its
beneﬁts (including freedom from a machine and elec- The toll of coincident disease—especially blindness,
trical outlets and ease of travel) against its disadvan- limb amputations, and cardiac disease—complicates
tages (unremitting attention to ﬂuid exchange, constant rehabilitation. Diabetic ESRD patients have a higher
risk of peritonitis, and disappearing exchange surface) death rate due to cardiac decompensation, stroke,
for each patient.11 sepsis, and pulmonary disease than do nondiabetic
Following a kidney transplant, patient survival at Table 3 lists the major comorbid conditions of con-
cern in the management of diabetic ESRD patients.
1 and 2 years in diabetic recipients is now similar to
Retinal, cardiovascular, and lower-limb diseases rank
that of the overall ESRD transplant population.9
at the top of the list. We routinely collaborate with an
Statistical superiority in survival after a kidney trans-
ophthalmologist so that laser and/or vitreous surgery
plant compared with dialytic therapy does not tell the
whole story (Figure 1), however, as rehabilitation is
also vastly improved after transplant. Enhanced quality Table 3. Diabetic Complications That Persist
of life (QOL) makes kidney transplant the distinctly and/or Progress During ESRD
favored treatment when presented to newly evaluated
1. Retinopathy, glaucoma, cataracts
diabetic ESRD patients younger than age 60 (Table 2).
More than half of diabetic kidney transplant recipients 2. Coronary artery disease, cardiomyopathy
in most series live for at least 3 years, and many 3. Cerebrovascular disease
survivors return to occupational, school, and home 4. Peripheral vascular disease: limb amputation
5. Motor neuropathy, sensory neuropathy
Unfortunately, bias in assignment to a speciﬁc treat- 6. Autonomic dysfunction: diarrhea,
ment may have prejudiced the favorable view of kid- dysfunction, hypotension
ney transplants. For example, studies in which the 7. Myopathy
mean age of transplant patients is a decade younger
than the CAPD or HD groups are likely to discern bet-
ter functional status in the younger group.11 (From Friedman,11 1999).
are integrated into the comprehensive management of vincingly demonstrated that treatment of anemia with
these patients. Similarly, we consult—even in asympto- rHuEPO reduces morbidity and mortality in patients
matic patients—a cardiologist familiar with uremia in with ESRD who are undergoing dialysis.22 Correction of
diabetic patients. Coronary angiography (if indicated) is anemia, therefore, has become a key component in
a valuable tool for detecting patients for whom prophy- preserving work, school, and home responsibilities in
lactic coronary artery angioplasty or bypass surgery is patients afﬂicted with CKD in diabetes. A well-
likely to extend life. A podiatrist on our team delivers designed, randomized, prospective trial will help to
routine foot care. By regular surveillance of patients at convince physicians that treating anemia earlier can
risk of major lower-extremity disease, the podiatrist has reduce the complications and perhaps even delay the
sharply reduced the chance of amputations, a compli- progression of CKD.
cation we noted in about 20% of patients who do not
receive podiatric care. Future directions of therapy
Survival rates are continually improving for diabetic
Pre-ESRD intervention ESRD patients on dialytic therapy or after kidney trans-
The Diabetes Control and Complications Trial plantation. Progress in developing new therapies
found that “intensive diabetes treatment”—designed to reﬂects multiple small advances in understanding the
achieve blood glucose levels as close to normal as pos- pathogenesis of extrarenal micro- and macrovasculopa-
sible—slows the progression of nephropathy, retinopa- thy in diabetes, coupled with safer immunosuppres-
thy, and neuropathy in diabetic patients.17 Several other sion. Trials based on prevention of tissue and organ
interventions have also been found to be effective in damage resulting from hyperglycemia and oxidative
decreasing the rate of development of nephropathy in stress are now in progress at multiple centers. As clari-
diabetic patients, including blood pressure reduction ﬁcation of the perturbed biochemical reactions under-
and dietary protein restriction. Treatment with antihy- lying the pathogenesis of diabetic vasculopathy pro-
pertensive agents (especially angiotensin-converting ceeds, we believe a way will be found to block end-
enzyme inhibitors), even in normotensive diabetic organ damage without correcting hyperglycemia,
patients, can decrease microalbuminuria, postpone the meaning that diabetic nephropathy, like other vasculo-
evolution from microalbuminuria to overt proteinuria pathic complications, may be entirely preventable.
(macroalbuminuria), decrease protein excretion in
patients with overt proteinuria, and slow the anticipated Accelerated synthesis and tissue deposition of
decline in the glomerular ﬁltration rate (GFR).18 Dietary advanced glycosylation endproducts (AGEs) has been
protein restriction can decrease microalbuminuria, proposed as a contributing mechanism in the patho-
overt proteinuria, and the anticipated rate of genesis of clinical complications in diabetes23 and in
decline in the GFR.18 the complications of CKD.24 AGEs are the end result
of a nonenzymatic reaction called the Maillard reaction
CKD induces mild anemia that becomes more that occurs between ambient glucose and primary
severe as kidney disease progresses, no matter what amino groups on proteins.25 This reaction results in
the primary cause of kidney functional loss. In diabetic glycated residues called Amadori products, which, after
nephropathy, the onset of anemia caused by erythro- a series of dehydration and fragmentation reactions,
poietin deﬁciency can occur early, during the period are converted into AGEs.
of chronic renal insufﬁciency (CRI).19 A 1999 report
showed that only 23% of all patients who begin dialysis Studies in rodents suggest that AGEs exert their
with a hematocrit level of <28% received treatment toxicity by impairing nitric oxide-mediated processes,
with recombinant human erythropoietin (rHuEPO) including neurotransmission and blood ﬂow in small
before reaching ESRD.20 vessels.26 Aminoguanidine, an inhibitor of nonenzym-
atic glycosylation and nitric oxide quenching, may
Anemia affects the patient with diabetes and CKD in offer a means for reducing the formation and toxicity
a number of ways. A lower hemoglobin level reduces of AGEs.26, 27 Separate multicenter trials in types 1 and
oxygen carriage, which in turn impinges on various 2 diabetics whose proteinuria is attributable to nephro-
aspects of QOL, including the ability to do work, think pathy are in progress. This approach is attractive
clearly, and enjoy life.21 This decrease in QOL may be because it bypasses the need to achieve euglycemia,
reversed with rHuEPO treatment.21 It has been con- which is often unattainable.
Alternatively, several exciting and entirely fresh tion. No matter which ESRD therapy has been elected,
approaches to attaining euglycemia are now being pur- effective rehabilitation in diabetic ESRD patients is con-
sued. For example, after the function of the insulin tingent on recognition and management of comorbid
receptor was elucidated, a search was initiated through conditions. There is every reason to believe that the
50,000 compounds to unearth any that might stimulate “end of diabetes” as an important clinical disorder will
the receptor. A compound extracted from the Kenyan soon be upon us. Just as poliomyelitis yielded to vac-
cines and now is presented as an historical disease to
fungus Pseudomassaria was discovered to have the
medical students, so will all of the terrible complica-
capacity to mimic insulin action in biochemical and
tions of diabetes be a footnote to a bygone era.
cellular assays, acting as an “insulin pill.”28 In two
mutant mouse models of diabetes, oral administration References
of this compound lowered blood glucose levels by up 1. King H, Aubert R, Herman W. Global burden of diabetes, 1995-2025:
prevalence, numerical estimates, and projections. Diabetes Care.
to 50%, equivalent to the reduction attained with 1998;21:1414-1431.
current oral antidiabetic therapies.
2. National Institutes of Health. National Diabetes Information
Clearinghouse, Diabetes Statistics. Bethesda, Md: National Institute
The novel concept of cell receptor modiﬁcation to of Diabetes and Digestive and Kidney Diseases, NIH Publication No.
alter downstream signaling molecules is also being
extended to organ transplant recipients in what has 3. Ismail N, Becker B, Strzelczyk P, Ritz E. Renal disease and hyperten-
sion in non-insulin-dependent diabetes mellitus. Kidney Int.1999;
been termed “the new immunology.”29, 30 For individuals 55:1-28.
with diabetes whose vasculopathy is still best managed
4. US Renal Data System. USRDS 2001 annual data report. National
by transplant, this technology offers potential promise Institutes of Health, National Institute of Diabetes and Digestive
for long-term successful “tolerance” of SPK allografts.15 and Kidney Diseases. 2001.
Until that occurs, the ESRD patient with type 1 dia- 5. Hasslacher C, Ritz E, Wahl P, Michael C. Similar risks of nephropa-
thy in patients with type I or type II diabetes mellitus. Nephrol Dial
betes still would be well advised to consider an SPK Transplant. 1989;4:859-863.
transplant as the preferred therapy for curing an inex-
6. Biesenback G, Janko O, Zazgornik J. Similar rate of progression in
orable disease. Within the next few years, however, the predialysis phase in type I and type II diabetes mellitus.
there is a high probability that either insulin receptor Nephrol Dial Transplant. 1994;9:1097-1102.
stimulation or restoration of islet function by injecting 7. US Renal Data System. USRDS 1997 annual data report. Bethesda,
Md: National Institutes of Health, National Institutes of Diabetes
allogenic or xenogenic islet beta cells will end the “big
and Digestive and Kidney Disease;1997.
surgery” required for segmental or whole-pancreas
8. Friedman E. Diabetic Nephropathy. In: Schrier RW, ed. Atlas of
grafting, simplifying or eliminating the stress of Diseases of the Kidney. Denver: Blackwell Science;1999:1-20.
surgery while attaining the same objective.15 For those
9. US Renal Data System. USRDS 2000 annual data report. National
with type 2 diabetes, I believe it is likely that an “all- Institutes of Health, National Institute of Diabetes and Digestive
oral” regimen that forestalls vasculopathic complica- and Kidney Diseases. 2000.
tions will be developed. 10. Abourizk N, Dunn J. Types of diabetes according to National
Diabetes Data Group Classiﬁcation:limited applicability and need
to revisit. Diabetes Care. 1990;13:1120-1122.
11. Friedman E. Diabetic nephropathy: fresh perspectives. Facta
The rate of kidney functional decline in diabetic Universitatis, Medicine and Biology Series (Yugoslavia). 1999;
nephropathy is slowed by normalization of hyperten-
sive blood pressure, establishment of euglycemia, and 12. Ifudu O, Paul H, Mayers J, et al. Pervasive failed rehabilitation in
center-based maintenance hemodialysis patients. Am J Kidney Dis.
reduced dietary protein intake. When compared to 1994;23:394-400.
patients with other causes of ESRD, the diabetic patient
13. Rubin J, Hsu H. Continuous ambulatory peritoneal dialysis: ten
sustains greater mortality and morbidity due to con- years at one facility. Am J Kidney Dis. 1991;17:165-169.
comitant (comorbid) systemic disorders, especially 14. Sollinger H, Ploeg R, Eckhoff D, et al. Two hundred consecutive
coronary artery and cerebrovascular disease. A func- simultaneous pancreas-kidney transplants with bladder drainage.
tioning kidney transplant provides the uremic diabetic
patient better survival with superior rehabilitation than 15. Sutherland DE, Gruessner RW, Dunn DL, et al. Lessons learned
from more than 1,000 pancreas transplants at a single institution.
does either CAPD or maintenance HD. For some dia- Ann Surg. 2001;233:463-501.
betic ESRD patients, a combined pancreas and kidney 16. Markell MS, Friedman EA. Diabetic nephropathy. Management of
transplant may cure diabetes and permit full rehabilita- the end-stage patient. Diabetes Care. 1992;15:1226-1238.
17. Diabetes Control and Complications Research Group D. Effect of 24. Aso Y, Inukai T, Tayama K, Takemura Y. Serum concentrations of
intensive therapy on the development and progression of diabetic advanced glycation endproducts are associated with the development
nephropathy in the Diabetes Control and Complications Trial. Kidney of atherosclerosis as well as diabetic microangiopathy in patients with
Int. 1995;47:1703-1720. type 2 diabetes. Acta Diabetol. 2000;37:87-92.
18. Nathan DM. Long-term complications of diabetes mellitus. N Engl J 25. Wautier JL, Guillausseau PJ. Advanced glycation end products, their
Med. 1993;328:1676-1685. receptors and diabetic angiopathy. Diabetes Metab. 2001;27:535-542.
19. Bosman DR, Winkler AS, Marsden JT, et al. Anemia with erythro- 26. Bucala R, Tracey K, Ceram A. Advanced glycosylation products
poietin deﬁciency occurs early in diabetic nephropathy. Diabetes Care. quench nitric oxide and mediate defective endothelium-dependent
2001;24:495-499. vasodilation in experimental diabetes. J Clin Invest. 1991;87:432-438.
20. Obrador GT, Ruthazer R, Arora P, Kausz AT, Pereira BJ. Prevalence 27. Edelstein D, Brownlee M. Mechanistic studies of advanced glycosy-
of and factors associated with suboptimal care before initiation of dialy- lation end product inhibition by aminoguanidine. Diabetes. 1992;
sis in the United States. J Am Soc Nephrol. 1999;10:1793-1800. 41:26-29.
21. Revicki D, Brown R, Feeny D, et al. Health-related quality of life 28. Zhang B, Salituro G, Szalkowski D, et al. Discovery of a small mole-
associated with recombinant human erythropoietin therapy for predial- cule insulin mimetic with antidiabetic activity in mice. Science. 1999;
ysis chronic renal disease patients. Am J Kidney Dis. 1995;25:548-554. 284:974-977.
22. Harnett JD, Kent GM, Foley RN, Parfrey PS. Cardiac function and 29. Schwartz R. The new immunology - the end of immunosuppres-
hematocrit level. Am J Kidney Dis. 1995;25:S3-7. sive drug therapy? N Engl J Med. 1999;340:754-755.
23. Brownlee M, Cerami A, Vlassara H. Advanced glycosylation end 30. Guinan EC, Boussiotis VA, Neuberg D, et al. Transplantation of
products in tissue and the biochemical basis of diabetic complications. anergic histoincompatible bone marrow allografts. N Engl J Med.
N Engl J Med. 1988;318:1315-1321. 1999;340:1704-1714.
Review and commentary on the recent literature
Article title: Remission and regression in the nephropathy of type 1 diabetes when
blood pressure is controlled aggressively
Authors: Hovind P, Rossing P, Tarnow L, Smidt UM, Parving HH
Journal: Kidney Int. 2001;60:277-283
T here is a growing body of literature on
the nephro-pathy associated with diabetes
mellitus, encompassing natural history
and interventional studies, which suggests
that treatment of hypertension may result in reduction
in proteinuria and rate of loss of kidney function
of diabetic kidney disease, with the dual strengths of
using a reliable method for ascertaining GFR, and
having a fairly large sample size. Larger interventional
studies (such as the Modiﬁcation of Diet in Renal
Disease1 and Appropriate Blood Pressure Control in
Diabetes2 trials) have conﬁrmed the beneﬁt of blood
among patients with diabetic and nondiabetic kidney pressure lowering among patients with nondiabetic
disease. This observational study by Hovind and and diabetic kidney disease.
colleagues, of 301 patients with nephropathy due to
The mean baseline GFR of the study group was
type 1 diabetes, further contributes to this body of work.
fairly high, and it is unclear whether patients who pro-
The authors studied consecutive patients at a single gressed to end-stage renal disease within 3 years were
centerwho had a minimum of 3 years of follow-up, included in the study. If these patients were excluded,
with yearly assessment of albuminuria and glomerular the observed mean rate of decline of GFR is lower than
ﬁltration rate (GFR) using a 51Cr-EDTA plasma clear- would be expected if all patients were included. Thus,
ance technique. Remission was deﬁned as a decrease the study would have assessed the impact of blood
in albuminuria to <200 mg/min and ≥30% reduction, pressure and other factors in the lower-risk group
sustained for at least 1 year. Regression was deﬁned of slow progressors or nonprogressors.
as a decline of GFR <1 mL/min/year during the The authors’ conclusion that aggressive treatment of
observation period. hypertension results in remission and regression may
The mean rate of decline of GFR was 4.0 ± be too strongly stated, as there was a sizeable propor-
0.2 mL/min/year. There were 30 patients (10%) who tion of patients (N=30) who were spontaneously
were spontaneously normotensive throughout the normotensive in the regression group. Overall, this
study. Sixty-seven patients (22%) experienced group had a signiﬁcantly lower rate of decline of
regression and 92 (31%) entered remission. GFR (1.9 mL/min) compared with
Systolic and diastolic blood pressures were signiﬁ- the hypertensive patients requiring antihyperten-
cantly lower among patients with regression or remis- sive treatment (4.3 mL/min). In addition, only 40%
sion compared to those without. Among patients in the of patients achieved adequate blood pressure control
regression group, 49% obtained remission, while 36% (<140/90 mm Hg). It could be argued that the beneﬁt
in the remission group achieved regression. From the observed in the study possibly comes from remaining
persistent normotensive group (N=30), spontaneous normotensive, not from adequate treatment of hyper-
tension. It would have been of interest to evaluate the
remission and regression was noted in 10 and 14
interaction between blood pressure and use of anti-
patients, respectively, of whom none received antihy-
pertensive treament. Logistic regression analysis
showed an adjusted odds ratio of 2.14 (95% CI, 1.33 to Nevertheless, this is a well-performed study utilizing
3.44) for regression for every 10 mm Hg lower blood a reliable and reproducible measurement of kidney
pressure, as well as a higher odds for regression with function, which conﬁrms the potential beneﬁt of
lower albuminuria and better glycemic control. managing hypertension and diabetes even in
earlier stages of kidney functional impairment.
From these results, the authors conclude that
“aggressive antihypertensive treatment can induce Annamaria T. Kausz, MD
remission and regression in a sizable fraction of type 1 Boston, Massachusetts
diabetic patients,” and that “genuine normotensive...
patients with diabetic nephropathy have an excellent References
kidney prognosis.” 1. Hunsicker LG, Adler S, Caggiula A, et al. Predictors of the progres-
sion of renal disease in the Modiﬁcation of Diet in Renal Disease
Study. Kidney Int. 1997;51:1908-1919.
Commentary 2. Estacio RO, Jeffers BW, Gifford N, Schrier RW. Effect of blood
pressure control on diabetic microvascular complications in patients
This cohort study conﬁrms prior observational stud- with hypertension and type 2 diabetes. Diabetes Care. 2000;23
ies of the impact of various factors on the progression (suppl 2):B54-B64.
Article title: Effects of ramipril vs amlodipine on renal In September 2000, the amlodipine arm of the AASK
out comes in hypertensive nephrosclerosis: trial was terminated on the recommendation of the
a randomized controlled trial trial’s data and safety monitoring board, based on
Authors: Agodoa LY, Appel L, Bakris GL, et al results related to the treatment interventions with
Journal: JAMA. 2001;285:2719-2728 baseline proteinuria. External clinical studies released
data, after the initiation of AASK, suggesting that there
is a slowing of the progression of renal disease by ACE
he results of this study, from the African
American Study of Kidney Disease and inhibitors in participants with elevated proteinuria and
Hypertension (AASK) Study Group, sug- also suggesting that DHP-CCBs may elevate the level
gest that antihypertensive therapy with of proteinuria in patients and not slow the progression
ramipril offers greater beneﬁt in slowing deterioration of renal disease.
of kidney function than does amlodipine in patients
with hypertensive kidney disease and proteinuria. Commentary
Ramipril is an angiotensin-converting enzyme (ACE) A potential drawback to this study is that it used
inhibitor; amlodipine is a dihydropyridine calcium only half the number of patients in the amlodipine
channel blocker (DHP-CCB). The study also suggested arm, based on a pilot study showing a short-term
that ramipril may offer beneﬁt to patients without pro- increase in GFR. One could argue that too much
teinuria. emphasis was placed on the results of the pilot
The AASK trial was designed to evaluate the impact study, which included a total of only 94 patients.1
of each of three different classes of antihypertensive In addition, the decision to stratify patients into
drugs—ACE inhibitors, DHP-CCBs, and beta-blockers— subgroups according to their baseline UP/Cr was
made post hoc, making it seem somewhat arbitrary.
on the progression of hypertensive kidney disease in
African Americans. The patients (n=1,094), ranging in The primary outcome measured in this study was
age from 18 to 70 years, had glomerular ﬁltration rates the change in GFR. By combining patients with UP/Cr
(GFRs) of 20 to 65 mL/min/1.73 m2 and were enrolled above and below 0.22, however, the authors fail to
in the study between February 1995 and September provide convincing evidence that either agent is supe-
1998, with planned follow-up through September 2001. rior in slowing the decline in GFR. This demonstrates
how introducing artiﬁcial subdivisions after the fact
The authors performed subgroup analyses on partici-
can lead to problems in analyzing results from a ran-
pants with baseline urinary protein-to-creatinine ratio
domized controlled trial. According to the data, it
(UP/Cr) of >0.22 and ≤0.22, a value corresponding appears that amlodipine is better if UP/Cr <0.22,
approximately to the threshold of 300 mg/d for clinical- worse if UP/Cr >0.22, better if GFR >40 mL/min, and
ly signiﬁcant proteinuria. The UP/Cr cutpoint of 0.22 worse if GFR <40 mL/min. It would be difﬁcult to pro-
was chosen post hoc, but was selected because of clini- vide a biological explanation for the latter statement.
cal relevance independent of the AASK data, according
to the authors. What is convincing, however, is the disparity in
“hard” events between the two groups. The amlodipine
At follow-up, among participants with a UP/Cr of group clearly fares worse than the ramipril group with
>0.22, the ramipril group had a 36% slower mean regard to death and end-stage renal disease. The study
decline in GFR over 3 years and a 48% reduced risk of lacks a placebo group, so that it is a matter of specu-
clinical endpoints compared to the amlodipine group. lation whether this is because ramipril imparts beneﬁt,
Among the entire cohort, there was no signiﬁcant dif- amlodipine imparts risk, or both. At the very least, the
ference in mean GFR decline from baseline to 3 years study conﬁrms the belief that ACE inhibitors should be
among treatment groups. However, the ramipril group the antihypertensive agents of choice in CKD patients
had a 38% reduced risk of clinical endpoints and a 36% with hypertension, and, importantly, conﬁrms that this
slower mean decline in GFR after 3 months compared is also the case among African Americans.
to the amlodipine group.
Robert N. Foley, MD
The authors note that this study is the ﬁrst clinical
endpoint trial with sufﬁcient sample size to evaluate
the effect of inhibition of the renin-angiotensin-aldos-
terone system on kidney disease in African Americans. References
The results support the use of ramipril as initial
therapy in a multidrug regimen over a DHP-CCB-based 1. Hall WD, Kusek JW, Kirk KA, et al. Short-term effects of blood
pressure control and antihypertensive drug regimen on glomerular
regimen in patients with mild to moderate chronic ﬁltration rate: the African American Study of Kidney Disease and
kidney disease (CKD) and proteinuria. Hypertension Pilot Study. Am J Kidney Dis. 1997;29:720-728.
Scarring may play major role boxes that record every opening, they monitored
whether these patients took their medication over
in transplant rejection
a period of 4 weeks. Patients who took 80% or more
One of the body’s own mechanisms for wound of their prescribed doses were considered to be
healing might be a major contributor to chronic kidney compliant.
rejection following transplantation, according to a
study1 published in the New England Journal of Medicine. The study found no difference in compliance
between treatment-resistant and treatment-responsive
Tissue remodeling is known to be a prominent patients. Forty (82%) of the 49 treatment-resistant
feature of chronic kidney transplant rejection. Mesen- patients were compliant, while 46 (85%) of the 54
chymal cells (ﬁbroblasts and myoﬁbroblasts) are key treatment-responsive patients were compliant.
players in this process. However, no one knows
whether these cells originate locally or from precursor The authors conclude that other factors independent
cells from the recipient’s own circulation. Using DNA of a patient’s willingness to adhere to a treatment regi-
analysis to study biopsies from transplanted kidneys men are more relevant in explaining treatment resist-
that were undergoing chronic rejection, the authors ance in most patients, and that these factors should be
found that up to 38% of the mesenchymal cells in the examined to explain lack of response to antihyper-
allografts originated from the recipient rather than the tensive drugs.
donor. Donor mesenchymal cells were also present.
Unexpected treatment for type 1
The authors conclude that the presence of mes-
enchymal cells of host origin in the vascular and inter-
stitial compartments of kidney allografts undergoing Researchers at Harvard Medical School have found
chronic rejection provides evidence that a circulating an unexpectedly simple treatment for type 1 diabetes
mesenchymal precursor cell has the potential to in mice. In a study3 published in the Journal of Clinical
migrate to areas of inﬂammation. Investigation, the researchers were able to retrain the
immune system in order to halt the autoimmune
Compliance not an issue in treatment- process that causes the destruction of islet cells in
nonobese diabetic (NOD) mice.
For many patients with arterial hypertension, blood The study presents two key ﬁndings. First, the
pressure cannot be adequately controlled, despite treat- autoimmune cells in NOD mice are unusually sensitive
ment with antihypertensive drugs. Noncompliance to the cytokine tumor necrosis factor-α (TNF-α), which
with treatment is thought to be common in patients causes them to undergo apoptosis (programmed cell
with treatment-resistant hypertension. However, a death). Second, many of these same cells are unable
Swiss study2 reported in the British Medical Journal has to present self-antigens, a process that is crucial for pre-
found no difference in compliance between treatment- venting the development of autoimmune reactions.
resistant and treatment-responsive patients.
The Harvard team thus designed a two-pronged
According to one deﬁnition, treatment-resistant treatment strategy. First, they triggered the expression
hypertension is persistent high blood pressure of TNF-α in the NOD mice in an attempt to destroy
(>140/90 mm Hg for patients aged ≤60 years or the immune cells that had gone awry. They then trans-
>160/90 mm Hg for those aged >60 years) in spite planted spleen or pancreas cells from non-autoimmune
of treatment for a sufﬁcient duration with at least two mice in order to expose these mice to normal major
appropriate antihypertensive drugs. Various explana- histocompatibility complex class I (MHC-I)
tions have been given for treatment-resistant hyperten- self-antigens.
sion, including secondary hypertension, endogenous
resistance to treatment, and, foremost, noncompliance Ordinarily, transplants of insulin-producing pancre-
with antihypertensive drug regimens. atic islet cells from healthy donors do not survive for
very long in either NOD mice or humans. But the
To test how much of a role noncompliance actually TNF-α/MHC-I treatment not only reversed islet-cell
plays in resistant hypertension, the researchers studied autoimmunity in the NOD mice, it also restored endo-
103 patients who had been taking between two and genous pancreatic islet function to such an extent that
four drugs for at least 1 month. Using electronic pill normal blood glucose levels were maintained in up to
75% of animals after the treatment was discontinued Based on these results, the authors conclude that
and islet transplants were removed. cocaine should be considered as a cause of ESRD in
patients without a clear cause of kidney failure.
The authors conclude that it might be feasible to
apply this treatment regimen to humans with type 1 Oral bacterial supplements may reduce
diabetes as well. stone formation
High levels of oxalate in the urine are a major risk
New interactive CD-ROM available for
factor for kidney stones, and foods that contain this
children with kidney disease chemical appear to exacerbate the problem. Increased
The Starbright Foundation has created a new CD- intestinal absorption of oxalate also may play a role.
ROM titled "Living with Kidney Disease," for children Because some normal intestinal bacteria are known to
and teenagers with kidney disease. This multimedia metabolize oxalate in the gut, which in turn limits its
program offers information on everything from med- absorption, Italian researchers recently conducted a
ications, diet, and dialysis to tips from peers and what study5 to see whether lactic acid bacteria might help
to expect before and after a transplant. reduce oxaluria in patients who had formed calcium-
The new, interactive CD-ROM is part of the
Starbright Explorer Series. The series also includes Six patients were fed a freeze-dried mixture contain-
CD-ROMs for other serious medical conditions, such ing the bacterial strains Lactobacillus acidophilus, L plan-
as cystic ﬁbrosis and sickle cell anemia. tarum, L brevis, Streptococcus thermophilus and
Biﬁdobacterium infantis for 4 weeks. At the end of that
The Starbright Foundation is a nonproﬁt organ-
time, urinary oxalate excretion was measured. The
ization, chaired by Steven Spielberg and Norman
team also studied the ability of each of the bacterial
Schwarzkopf, that creates programs designed to
strains to degrade oxalate and grow in oxalate-contain-
empower children with serious medical conditions
to address the psychosocial challenges that accompany ing media.
The researchers found that oxalate excretion was
More information on the Starbright Explorer Series is reduced in all six of the patients, with mean levels
available at www.starbright.org. falling from 55.5 mg/d to 33.5 mg/d. They conclude
that treatment with a high concentration of freeze-
Cocaine use, hypertension, and end- dried lactic acid bacteria can greatly reduce the
stage renal disease urinary excretion of oxalate, and that this biological
Cocaine use has been associated with both acute kid- manipulation of endogenous digestive microﬂora may
ney failure and hypertension (HTN), but recent data be a novel approach for the prevention of urinary
also suggest it may lead to a chronic insidious form of stone formation. CKD
kidney failure. In a recent cross-sectional study4 of
urban patients who were undergoing outpatient
1. Grimm P, Nickerson P, Jeffery J, Savani RC. Neointimal and tubu-
hemodialysis, researchers from the University of
lointerstitial inﬁltration by recipient mesenchymal cells in chronic
California, Los Angeles, compared the rates of cocaine renal-allograft rejection. N Engl J Med. 2001;345:93-97.
use in patients with and without HTN-related
2. Nuesch R, Schroeder K, Dieterle T, Martina B, Battegay E. Relation
end-stage renal disease (HTN-ESRD). between insufﬁcient response to antihypertensive treatment and
poor compliance with treatment: a prospective case-control study.
The researchers found that 89% of the cocaine users BMJ. 2001;323:142-146.
enrolled in the study had been diagnosed with HTN- 3. Ryu S, Kodama S, Ryu K, Schoenfeld DA, Faustman DL. Reversal of
ESRD compared with only 46% of those who did not established autoimmune diabetes by restoration of endogenous beta
cell function. J Clin Invest. 2001;108:63-72.
report cocaine use. Of the 113 subjects with HTN-
ESRD, 43% had a history of cocaine abuse. Those HTN- 4. Norris KC, Thornhill-Joynes M, Robinson C, et al. Cocaine use,
hypertension, and end-stage renal disease. Am J Kidney Dis.
ESRD patients who reported cocaine use were also 2001;38:523-528.
signiﬁcantly younger than those who had not used
5. Campieri C, Campieri M, Bertuzzi V, Swennen E, Matteuzzi D.
cocaine, and had also been hypertensive for a shorter Reduction of oxaluria after an oral course of lactic acid bacteria at
period of time before they needed dialysis. high concentration. Kidney Int. 2001;60:1097-1105.
February 7 — 9
Title: 27th International Stroke Conference. Sponsor: Stroke Council of the
American Heart Association. Location: Henry B. Gonzalez Convention Center,
San Antonio, Texas. Website: http://www.strokeconference.org/index.oft
February 28 — March 2
Title: International Society of Renal Nutrition and Metabolism in Renal Disease:
11th International Congress on Nutrition and Metabolism in Renal Disease
Location: Nagoya, Japan. E-mail: firstname.lastname@example.org
March 2 — 6
Title: Annual Conference on Dialysis. Location: Tampa, Florida Phone: (573) 882-
4105. Website: http://muextension.missouri.edu
March 23 — 26
Title: Renal Physicians Association/Research and Education Foundation (RPA/REF)
Annual Meeting. Location: Washington, DC. E-mail: email@example.com
April 22 — 26
Title: The Genomics Revolution: Bench to Bedside to Community, and
the 42nd Annual Conference on Cardiovascular Disease Epidemiology and
Prevention. Location: Hawaii Convention Center, Honolulu, Hawaii.
April 26 — May 3
Title: 3rd Annual Joint Meeting and Scientiﬁc Sessions, American Society
of Transplantation/American Society of Transplant Surgeons (AST/ASTS).
Location: Washington, DC. E-mail: firstname.lastname@example.org
May 23 — 26
Title: 33rd National Symposium, American Nephrology Nurses’ Association
(ANNA). Location: Orlando, Florida. Website: http://www.annanurse.org
June 2 — 5
Title: 13th World Congress. Sponsor: International Society for the Study
of Hypertension in Pregnancy (ISSHP). Location: Toronto, Canada.
July 14 — 17
Title: 2002 Congress of the European Renal Association (ERA)/European Dialysis
and Transplant Association (EDTA). Location: Copenhagen, Denmark.
Treatment of hypertension
Your Opinion presents the results of a reader survey that welcomes the participation of all nephrologists
(see next issue’s survey below). For this issue, a randomly selected group of nephrologists were asked about
hypertension and sexual dysfunction as they relate to renal disease. Here are their aggregate responses.
What percentage of your patients have diabetes What percent of your patients have DM
mellitus (DM) as a cause of renal disease? whether or not it is the cause of renal disease?
% of Nephrologists surveyed
% of Nephrologists surveyed
20% 21% 0.1
0% 0% 0% 0% 0%
0% 0% 0% 0% 0% 0% <10% 10-25% 26-50% 51-75% >75%
<10% 10-25% 26-50% 51-75% >75%
% of Patients
% of Patients
What percent of your patients with diabetes Rank your preference of antihypertensive
have a regular endocrinologist who class in diabetic patients with chronic
participates in their care? kidney disease (CKD):
% of Nephrologists surveyed
0.6 0% 20% 40% 60% 80% 100%
% of Nephrologists surveyed
0.3 28% 3 ARBs
22% 22% Dihydropyridine CCBs
6% 6% 6%
<10% 10-25% 26-50% 51-75 >75%
% of Patients Choices ranked from 1 to 6
Comment for publication If you answered "Yes" above, please check the items
offered in your program, and the approximate pecen
The nephrologists in this survey were asked: What tage of new patients who receive them.
are the barriers to nephrologists providing the principal
care related to diabetes for end-stage renal disease or
Check all that apply Approximate % of
CKD patients? Some of the responses included:
Limited resources in terms of time, patient load, Written material ____ %
and the number of parameters that need to be man- Videotapes ____ %
aged per patient
Direct teaching by physician ____ %
Lack of a system for coordinating care between
nephrologist, diabetes clinic and support Direct teaching by nurse educator ____ %
staffLimitations imposed by managed care Other _ ____ %
2. Please rank each of these challenges 1 to 4 in terms
Poor referral rate, lack of access to these patients
of how large an obstacle they are to patient education
Inability to track the detailed management of these (1 = signiﬁcant obstacle; 4 = no obstacle).
patients, which needs to be multi-disciplinary
Note—"Your Opinion" is an informal poll that makes no
claims of statistical signiﬁcance Circle the appropriate number in each row
(1 = signiﬁcant obstacle; 4 = no obstacle):
We want your opinion for our next issue!
Cultural/language barriers 1 2 3 4
Fax or mail us your responses to the following questions Lack of interest/
regarding your patients with diabetes mellitus (DM): ability to focus by patients 1 2 3 4
Lack of adequate teaching
1. Do you have an educational program for new
materials 1 2 3 4
patients (check one)?
Lack of time by
Yes ____ No ____ dialysis staff 1 2 3 4
Note—“Your Opinion” is an informal poll that makes no claims of statistical signiﬁcance.
Your comment for publication
What are the barriers to nephrologists providing
the principal care related to diabetes for ESRD
or CKD patients?
Fax the completed survey to 973-263-3952 or send to: CKD Survey, HealthVizion
Communications, 20 Waterview Blvd., Parsippany, NJ 07054-1295.
diagnostic Submitted by
challenge Jill Lindberg, MD
New Orleans, Louisiana
Table 1: Physical Examination Test Results
Test November 1996 February 1999
Weight (lb) 104 88
Blood pressure (mm Hg) 120/80 100/70
Peripheral edema None None
Kyphosis + with tenderness + severe without
over T3, T4 tenderness
Pallor _ +
EKG +LVH +LVH with BBB
DEXA standard deviations _3.5 _4.0
below young normal at the
Chest x-ray Positive T4-T5 Pulmonary edema
compression fractures No new compression
Table 2: Laboratory Test Results
Test/Findings November 1996 February 1999
Creatinine (mg/dL) 1.6 2.2
Creatinine clearance (cc/min) 30.0 12.0
Hematocrit (%) 32.0 29.0
Serum calcium (mg/dL) 8.0 7.8
Albumin (g/dL) 3.8 2.9
Phosphorus (mg/dL) 2.0 4.0
PTH (ng/ml) 122.0 380.0
Urine protein (mg/day) 400.0 502.0
Urinalysis Multiple white cell casts,
negative red cell casts
WBC Normal with 3.290 Normal with 8.790
INITIAL VISIT: NOVEMBER 1996 20-year history of frequent use of over-the-counter
analgesics, including headache powders.
Case description: A 76-year-old white woman pre- Family history: Negative for renal insufﬁciency;
sented to the Osteoporosis Clinic for evaluation of positive for osteoporosis in multiple family members.
severe osteoporosis and spontaneous compression frac- Two to three alcoholic drinks per day; 1 pack of
tures. She complained of severe back pain, and had a cigarettes per day.
Medications: Advil® (ibuprofen, Whitehall-Robins); workup of her renal insufﬁciency were negative. She
headache powders, including BC® Headache Powder was very upset that the physical exam and history had
(aspirin, salicylamide, and caffeine, GlaxoSmithKline) focused on her renal insufﬁciency.The patient refused
and Goody’s® Headache Powder (acetaminophen, to return for kidney biopsy and follow-up. She was lost
aspirin, and caffeine, GlaxoSmithKline). to follow-up until her visit in 1999.
Physical examination: See Table 1. Blood pressure
was 120/80 mm Hg; lungs were clear; heart PMI (point FOLLOW-UP: FEBRUARY 1999
of maximal intensity) was displaced laterally to an
anterior axillary line; extremities had no edema; back Patient returned with increased creatinine levels as
had positive tenderness over T3 and T4. seen in Table 2. In addition, she was very anemic and
complained of severe shortness of breath.
Lab results: See Table 2. In addition, thoracic spine
ﬁlms showed two compression fractures. Renal Physical exam: Blood pressure was 100/70 mm Hg;
ultrasound revealed increased echogenicity in both kid- weight had dropped to 80 pounds. Lung exam revealed
neys with kidneys slightly reduced in size to 8.7 cm rales halfway up bilaterally; heart was positive S3; PMI
bilaterally. was displaced laterally into the anterior axillary line.
Treatment adjustments: Treatment with subcuta- Test results: Renal ultrasound was repeated, and
neous calcitonin, 100 units 3 times per week, was revealed increased echogenicity. Kidney size was
initiated, along with Citracal® Caplets +D (calcium now 8 cm bilaterally. Urinalysis revealed persistent
citrate with vitamin D3, Mission Pharmaceuticals). The white cell casts. Echocardiogram revealed an ejection
patient was instructed to return within 1 month for fol- fraction of 20%.
low-up of her renal insufﬁciency and education in the Outcome: The patient refused renal biopsy. She
Healthy Start program. She also was asked to return in was initiated on hemodialysis after diuresis was
2 weeks for a kidney biopsy, as all serology tests and unsuccessful.
Diagnostic Challenge: What was the most likely cause of thispatientÌs renal insufficiency?
What was the most likely cause of her severe left ventricular
dilatation and resulting congestive heart failure?
Answer to Diagnostic Challenge in CKD Vol 1, Number 2. Syndrome of inappropriate
secretion of antidiuretic hormone. Submitted by Richard Sherman, MD, New Brunswick, New Jersey
Click here for the audio answer to this challenging case.
Hyponatremia in an AIDS patient in this setting capable of normal sodium retention given an appropri-
should prompt consideration of 4 major diagnoses: (1) ate volume stimulus; SIADH is not a salt-wasting
so-called dilutional hyponatremia due to volume deple- disorder.
tion; (2) the syndrome of inappropriate secretion of The hyponatremia improved with saline because the
antidiuretic hormone (SIADH); (3) cerebral salt wast- SIADH was mild and perhaps becaused it was coupled
ing; and (4) adrenal insufﬁciency. The lower urinary with gastrointestinal water losses. The renal insufﬁ-
sodium at presentation effectively excludes the latter 2 ciency (not pursued here for the purposes of this dis-
diagnoses. The patient is clearly volume depleted. He cussion) can make the diagnosis of SIADH problematic
has orthostatic hypotension and a low jugular venous largely because of the uncertainty that is introduced
pressure; this probably accounts for the low urinary regarding sodium handling by the diseased kidney.
sodium and high urinary osmolality at presentation. However, in this case, there's clear evidence that sodi-
However, after several days, the patient, despite um conservation is not impaired by the kidney disease.
remaining hyponatremic, now has substantial amounts Also notable is the relatively low uric acid level
of sodium and chloride in the urine and continued evi- which may be seen in both SIADH and cerebral salt-
dence of vasosuppressant secretion; that is, his urine wasting. However, it is not widely appreciated that
osmolality is 410 mOsm/L. His condition can no longer hypouricemia is also seen with guaifenesin
be explained by severe volume depletion. It is likely (Robitussin), which is uricosuric. The drug was the
that the volume depletion was superimposed on mild most common cause of low serum uric acid in the
SIADH in this patient. The patient with SIADH is quite Boston Collaborative Drug Study.