Twelve shifting paradigms in diabetic renal disease and

hypertension
Carl Erik Mogensen
Medical Department M, Aarhus University Hospital, Nrrebrogade 44, DK-8000 Aarhus C, Denmark
di a b e t e s r e s e a r c h a nd c l i ni c a l p r a c t i c e 8 2 s ( 2 0 0 8 ) s 2 s 9
a r t i c l e i n f o
Keywords:
Diabetes
Hypertension
Microalbuminuria
Hyperltration
Reninangiotensin
system
Dedicated to Ryuichi Kikkawa.
a b s t r a c t
In the last 30 years we have seen considerable progress in the management of patients with
diabetes, in particular with diabetic renal disease. Anumber of paradigms have been broken
down, namely the following, as a consequence, clinical care has improved dramatically.
1. Signicant renal involvement and albuminuria is rare in patients with essential hyper-
tension.
2. High GFR is good for prognosis.
3. Only proteinuric diabetic patients have a poor prognosis.
4. Microalbuminuria only predicts renal disease.
5. Reducing blood pressure may cause low perfusion in the kidney and other organs with
long-term negative effect, especially on the glomerular ltration rate.
6. Only in the presence of high blood pressure, should microalbuminuric patients receive
anti-hypertensive treatment, including blockade of the RAS.
7. Only reducing blood pressure by blocking RAS in diabetes is relevant and justied.
8. Normoalbuminuria as indicated in the present denition is normal.
9. ACE-I or ARB can only be used separately.
10. Diastolic blood pressure and later systolic pulse pressure are the best parameters for
blood pressure recording.
11. Microalbuminuria is the strongest risk marker in patients with type 1 diabetes.
12. Screening for microalbuminuria is relevant, but follow-up was not proposed (also
regarding microalbuminuria).
In the present situation, it is well-known that patients with essential hypertension may
sometimes have microalbuminuria, and it is known that it predicts a poor prognosis.
Interestingly, in type 1 diabetes, hyperltration is a marker for poor prognosis related to
metabolic control. Thus hyperltration is a marker for bad development, but microalbu-
minuria (below the proteinuric level) is also associated with a poor prognosis.
It was originally believed that microalbuminuria only predicts renal disease. However,
surprisingly it predicts as well cardiovascular disease and early mortality. The story about
bloodpressure andprogressionof renal disease is interesting, because it was earlier believed
that a certain high blood pressure was mandatory for preservation of the renal function.
This appeared to be a completely wrong concept.
The data regarding microalbuminuria suggest that patients with microalbuminuria
should receive anti-hypertensive treatment, even patients with so-called normal blood
pressure. This was conrmed in several trials and also included in the guidelines. Reducing
E-mail address: carl.erik.mogensen@ki.au.dk.
avai l abl e at www. sci encedi r ect . com
j our nal homepage: www. el sevi er . com/ l ocat e/ di abr es
0168-8227/$ see front matter # 2008 Published by Elsevier Ireland Ltd.
doi:10.1016/j.diabres.2008.09.029
1. Introduction
Over the past few decades there have been radical changes in
the management of patients with hypertension, in particular
as regards diabetic patients, and mostly as regards diabetic
patients with early renal disease. This short essay will
summarize progress; in general, the medical treatment of
these patients has very much changed and prognosis has
improved remarkably by glycemic control [13], that should not
be too tight according to the ACCORD study. The progress in
this area will be discussed in the light of the concenpts of
medical paradigms and paradigm-shifts [47].
2. Paradigm 1
2.1. Signicant renal involvement and albuminuria is rare
in patients with essential hypertension
So-called malignant hypertension was once well-described in
the ancient literature. For years this condition has been very
rare in societies with an efcient health care system although
screening for hypertension is not always done systematically.
The general belief around 1970 was that patients with
essential hypertension do not show renal involvement
manifested as reduced renal function (e.g. proteinuria/
albuminuria and/or increased serum-creatinine).
However, several studies inthe 1970s after the introduction
of radioimmunoassay for albumin in the urine show that
microalbuminuria was not uncommon, in poorly treated
hypertensive patients. Abnormal albuminuria may be normal-
ized by efcient anti-hypertensive treatment [7,36,41].
New papers such as HOPE [43] and RENAAL [15] and
other studies show that albuminuria is a continuum
[4,16,17,31,36,43] just as it is the case with most risk factors
such as blood pressure, glycemia, and lipid levels.
Consequently the once prevailing paradigm is not correct.
It is clear that borderline and abnormal albuminuria can be
found in many patients with hypertension, especially if they
have other complications. Indeed in the LIFE-study and in
other studies it was shown that higher the level of albumi-
nuria, the poorer prognosis [3,37]. Reduction of albuminuria
indicates a better prognosis incontrast to those who have high
or even higher values before and after treatment [45].
3. Paradigm 2
3.1. High GFR is good for prognosis
The recent guidelines [38] from the National Kidney Founda-
tion and the American Society of Nephrology classify patients
according to levels of estimatedGFR, the lower, the worsethe
higher, the better. Reduced renal function indicates a poor
prognosis, but so far there is with this parameter no clear-cut
intervention strategies based upon clinical trials, only epide-
miology. The classication does not take the phenomenon of
hyperltration into consideration, mainly seen in diabetes [23]
which has been originally documented over the past decades,
based mainly upon original experimental studies by Brenner
and co-workers [8].
The paradigm therefore does not seem correct any longer,
because in patients with type 1 diabetes, hyperltration,
dened e.g. as a GFR higher than 140 ml/min (corrected to
1.73 m
2
body surface area) indicated a poor prognosis (Table 1)
[5,23]. GFR is usually well-preserved in microalbuminuria with
type 1 diabetes with no tendency to decline with higher degree
of microalbuminuria [10]. In type 2 diabetes, hyperltration is
seen quite often in young patients (e.g. the PIMA Indians), and
also to a limited extent in elderly patients [20,42]. In
population-based studies from the Netherlands it has also
been suggested that increased GFR might relate to increased
blood pressure is important, but it appeared to be especially benecial to block the renin
angiontensin system, and it is clear that albuminuria is a continuous variable and is also a risk
factor. Earlier it was suggested to use ACE-inhibitors or ARBs. Nowit is clear that it is possible to
use a combination, with good theoretical background.
In the history of hypertension, it was earlier believed that diastolic blood pressure was most
important, but later on it was generally accepted that systolic is a better predictor and the goal
for treatment and pulse pressure may be even better.
Not only is microalbuminuria an important risk marker, but it is as well clear that regression
of microalbuminuria is a good marker for a better prognosis in patients. Microalbuminuria is
believed to be the strongest risk factor, but new studies actually suggest that a simple
parameter such as self-rated health is crucial along with other factors.
Regarding new developments, it is clear that new studies have led to several advancements
in management inpatients, for instance the Steno II study shows positive effect on mortality by
multifactorial intervention. Similarly, the ADVANCE study also showed positive effect on
mortality by more intensied anti-hypertensive treatment with an ACE-inhibitor. We are
eagerly awaiting the results from glucose arm in the ADVANCE study, especially in the light
of the ACCORDstudy showing increasedmortality withtoo strict glycemic control witha goal of
6% in HbA1c.
# 2008 Published by Elsevier Ireland Ltd.
di a b e t e s r e s e a r c h a nd c l i ni c a l p r a c t i c e 8 2 s ( 2 0 0 8 ) s 2 s 9 S3
risk [8]. Hyperltration(partly relatedto poor glycemic control)
thus prophesies a poor prognosis especially in T1 in diabetes
[23].
4. Paradigm 3
4.1. Only proteinuric diabetic patients have a poor
prognosis
It has beenwell-established that patients withproteinuria and
diabetes have a poor prognosis [46], as documented in follow-
up studies from the Steno and Joslin centres. The prognosis
has beenimproved due to efcient treatments, especially anti-
hypertensive treatment. However, newstudies in the early 80s
documented that it was not only proteinuria that indicates a
poor prognosis, also patients with so-called microalbuminuria
had an increased risk of progression to proteinuria and
reduced renal function with increased mortality [22].
This paradigmhas thus radically changed, and the concept
of microalbuminuria is now rmly established as a major risk
marker in both type 1 and type 2 diabetes and even in
population-based studies [31,32,33].
Microalbuminuria is dened as the excretion rate between
normal albumin excretion rate and the level characterized as
proteinuria. This level has been dened as an excretion rate
between 20 and 200 min or 30300 mg/24 h [30]. However, now
the level is indicated as albumin/creatinine ratio because
urine collections are cumbersome. Therefore in diabetes
clinics, the albumin/creatinine ratio is usually measured on
early morning urine [33].
5. Paradigm 4
5.1. Microalbuminuria only predicts renal disease
Originally it was hypothesised that microalbuminuria would
predict proteinuria and reduced renal function, but surpris-
ingly, it was shown, rst in type 2 diabetes, that micro-
albuminuria also strongly predicted early mortality [22], as
later conrmed in the UKPDS study by Adler et al. The same
was found in population-based studies [33]. Thus microalbu-
minuria is increasingly recognized as a general risk marker
probably reecting microvascular damage as endothelial
dysfunction or inammations in the small blood vessels
[33]. The abnormalities in the small blood vessels are most
easily detected in the urine where the transcapillary escape
rate can be measured in terms of urinary protein excretion.
However, it has to be mentionedthat there is a sizeable tubular
reabsorption [27], but still it is clear that measurement of
albumin in the nal urine is a very strong predictive marker.
6. Paradigm 5
6.1. Reducing blood pressure may cause low perfusion in
the kidney and other organs with long-term negative effect,
especially on the glomerular ltration rate
Once it was widely believed that anti-hypertensive treatment
would compromise renal circulation and thus be deleterious
to renal function [26,31]. Indeed, it was observed that
treatment with anti-hypertensive agents acutely reduced
GFR, and there was a fear that the renal function would be
reduced further and progressively over the years. It was
therefore suggested in several centres that physicians should
not reduce blood pressure in patients with diabetes and
hypertension or elevated blood pressure [26].
However, this paradigm appeared to be entirely wrong. In
the mid 70s studies started to suggest that rst of all
progression in renal disease as measured by exact fall rate
in GFR was closely related to blood pressure level (Fig. 1)
[27,28]. Subsequently it was shown that anti-hypertensive
treatment could reduce albuminuria and nally, it was shown
that anti-hypertensive treatment over the years reduced the
fall rate of GFR [9,11,24,27,28,29,34,40]. This was a major
breakthrough in the management of patients with type 1
diabetes. This treatment was rst based upon studies utilising
beta-blockers and diuretics and other anti-hypertensive
agents [11,29,40]. Later agents blocking the renninangioten-
sin system became available and relevant, although it was
clear that bloodpressure reductionper se shouldbe infocus [6].
Tagumi et al. [44] also broke a paradigm: ACE-inhibition was
useful in diabetic renal disease (49). The recent ADVANCE
study also emphasizes lowering of BP in type 2 diabetes even if
it is in the so-called normal range. Prevention or reduction of
microalbuminuria is a key nding, indicating a good prognosis
[1].
7. Paradigm 6
7.1. Only in the presence of high blood pressure, should
microalbuminuric patients receive anti-hypertensive
treatment, including blockade of the RAS
Within recent years it has become a paradigm that micro-
albuminuria is a major risk factor. Initially it was, however, not
advocated to treat these patients with anti-hypertensive
agents unless they had clearly increased blood pressure.
The denition of hypertension varied at levels higher than 140
or earlier 160 systolic. It was shownthat the progressionrate of
microalbuminuria was related to blood pressure. Therefore, it
was also a major breakthrough that it seemed possible to treat
these patients with persistent microalbuminuria (even with
so-called normal BP) and incipient diabetic nephropathy with
anti-hypertensive agents. When these studies were initiated,
it was not possible to block the renninangiotensin system
Table 1 Studies on predictive value of hyperfiltration in
T1 DM (progression to Microalb.).
Predictive GFR-level
Mogensen, NEJM 1984 158
Mogensen, Diabetes 1990 160
Dahlquist, NDT 2001 144
Amin, KI 2005 167
Mauer, Diabetes 2005 163
Please note consistency in predictive level.
di a b e t e s r e s e a r c h a nd c l i ni c a l p r a c t i c e 8 2 s ( 2 0 0 8 ) s 2 s 9 S4
with ACE-inhibitors or ARBs. And at the same time, GFR was
still well-preserved, quite often in the hyperltration range
[5,21,22]. Our studies also showed effect on glomerulopathy in
type 1 diabetes [24] (Fig. 2).
The paradigm-shift became apparent: treatment with
agents blocking the renninangiotensin system became more
acceptable (compared to beta-blockers) because of less side-
effects, and now it is proposed in all guidelines to treat
patients with microalbuminuria with agents blocking the
renninangiotensin system. New studies from Michael
Mauers group could not document any effect on structure
damage by blocking RAS in normoalbuminuric type 1 patients,
who are also known to have a low risk of progression [24].
8. Paradigm 7
8.1. Only reducing blood pressure by blocking RAS in
diabetes is relevant and justied
At present time it is advocated to start treatment with agents
that block the renninangiotensin system in patients with
Fig. 1 Correlation between BP and fall in GFR.
Fig. 2 Effect of antihypertensive treatment in type 1 patients with microalbuminuria.
di a b e t e s r e s e a r c h a nd c l i ni c a l p r a c t i c e 8 2 s ( 2 0 0 8 ) s 2 s 9 S5
microalbuminuria or proteinuria. However, the initial studies
were conducted at a point of time when only beta-blockers
and diuretics and a few other agents were available for anti-
hypertensive treatment [11]. Indeed, the rst studies showed
that the decline in renal function could be reduced and a small
and simple type of meta-analysis from Denmark of all
available studies at that time showed that the decline of
GFR was not better by blocking the ACEi as compared to other
anti-hypertensive agents [11]. It is, however, now clear that
treatment strategy is more easily performed with these new
agents because there are fewer side-effects. The most
noticeable side-effect in clinical practise by ACEi is a cough,
and in that case it will be relevant to switch to ARBs, but not
start initially with the more expensive ARBs. The renal effect
of these two classes of drugs is not too different, but if blood
pressure is not reduced by this strategy the effect is limited [6].
9. Paradigm 8
9.1. Normoalbuminuria as indicated in the present
denition is normal
Normoalbuminuria was and is dened as albumin excretion
below 20 mg/min or 30 mg/24 h. However, the excretion rate in
young normal individuals is usually around5 mg/min, but some
normal individualshavehigher values[30]. Thecut-off of 20was
denedbaseduponobservational studiesinpatientswithtype1
diabetes, where an excretion rate higher than 15 or 20 mg/min
usually was associatedwithprogression[24,25]. However, more
recent studies have shown that albuminuria in the upper
normal range is also a risk factor. This is not surprising because
albuminuria, just like other biological parameters, is a
continuous variable. It is thus clear that with so-called high-
normal values of albuminuria, there is a somewhat increased
risk of future cardiovascular and renal disease.
10. Paradigm 9
10.1. ACE-I or ARB
It has been widely practised either to use ACE-inhibitors or
ARBs as this is a useful and very feasible practise [14]. ACE-
inhibitors are substituted by ARBs in the case of cough.
However, using both agents at the same time was not
considered relevant [14,39]. In recent studies, it was docu-
mented that there might be a further effect of dual blockade in
diabetes. The CALM I study [35] showed that so-called dual
blockade with a combination of Candesartan and Lisinopril
was efcient in reducing the blood pressure and albuminuria.
In the next study, CALM II [2], it seemed possible to use the
double dose of ACE-inhibitors with comparable results.
11. Paradigm 10
11.1. Diastolic blood pressure and later systolic pulse
pressure are the best parameters for blood pressure recording
Years ago, by tradition, diastolic blood pressure was con-
sidered to be the main clinical parameter [35]. In the late 90s it
appeared that systolic blood pressure was a better predictor of
future cardiovascular damage (Fig. 3). Now new studies
suggest that pulse pressure may be an even better parameter
[18,19] (Fig. 4). The presence seems highly predictive of the
development and progression of renal disease and may be also
for cardiovascular morbidity and mortality in type 2 diabetic
subjects, althoughit is difcult to sort out the relevant effect of
the systolic blood pressure. Interestingly, according to new
studies, dual blockade has a pronounced effect on pulse
pressure compared to high-dose monotherapy and pulse
pressure may be more strongly related to central blood
pressure, transferred to the renal circulation [19].
Fig. 3 Effect of BP-reduction in ADVANCE and UKPDS.
di a b e t e s r e s e a r c h a nd c l i ni c a l p r a c t i c e 8 2 s ( 2 0 0 8 ) s 2 s 9 S6
12. Paradigm 11
12.1. Microalbuminuria is the strongest risk marker in
patients with diabetes
Microalbuminuria is widely accepted as a very strong risk
marker, but a new study in progress from Denmark shows
that very simple parameters suchas self-reportedhealthmay
be of better predictive value for advanced disease and
morbidity. A large body of literature is available on self-
reported health.
13. Paradigm 12
13.1. Screening for microalbuminuria is relevant, but
follow-up was not proposed (also regarding
microalbuminuria)
Screening for microalbuminuria has been proposed and
accepted by many guideline committees. This is highly
relevant, but new studies also document that reduction in
microalbuminuria is of considerable importance for a bene-
cial effect of treatment [12,20,45]. Therefore it is now
Fig. 4 Pulse pressure and survival in type 1 diabetic patients.
Fig. 5
di a b e t e s r e s e a r c h a nd c l i ni c a l p r a c t i c e 8 2 s ( 2 0 0 8 ) s 2 s 9 S7
recommended not only to screen for microalbuminuria, but
also to follow-up on treatment in order to see if there is a
sufcient decline in microalbuminuria during treatment.
Reduction in macroalbuminuria by anti-hypertensive treat-
ment correlates with subsequent fall rate in GFR.
Fig. 5 shows the paradigm circle as modied from Thomas
Kuhn. According to this paradigm circle concept, new
developments certainly may modify and improve our level
of knowledge.
This gure shows how paradigms constantly are in
development.
A key to references can be obtained in Refs. [4750].
Conict of interest
None.
r e f e r e n c e s
[1] ADVANCE Collaborative Group, Effects of a xed
combination of perindopril and indapamide on
macrovascular and microvascular outcomes in patients
with type 2 diabetes mellitus (the ADVANCE trial): a
randomised controlled trial, Lancet 370 (2007) 829840.
[2] N.H. Andersen, P.L. Poulsen, S.T. Knudsen, S.H. Poulsen, H.
Eiskjaer, K.W. Hansen, et al., Long-term dual blockade with
candesartan and lisinopril in hypertensive patients with
diabetes, Diab. Care 28 (2005) 273277.
[3] S. Basi, J.B. Lewis, Microalbuminuria as a target to improve
cardiovascular and renal outcomes, Am. J. Kidney Dis. 47
(2006) 927946.
[4] M. Bo hm, M. Thoenes, N. Danchin, P. Bramlage, P. La
Puerta, M. Volpe, Association of cardiovascular risk factors
with microalbuminuria in hypertensive individual: the i-
SEARCH global study, J. Hypertens. 25 (2007) 23172324.
[5] M.L. Caramori, P. Fioretto, M. Mauer, Enhancing the
predictive value of urinary albumin for diabetic
nephropathy, J. Am. Soc. Nephrol. 17 (2006) 339352.
[6] J.P. Casas, W. Chua, S. Loukogeorgakis, P. Vallance, L.
Smeeth, A.D. Hingorani, et al., Effect of inhibitors of the
renninangiotensin system and other antihypertensive
drugs on renal outcomes: systematic review and meta-
analysis, Lancet 366 (2005) 20262033.
[7] C.K. Christensen, Rapidly reversible albumin and b
2
-
microglobulin hyperexcretion in recent severe essential
hypertension, J. Hypertens. 1 (1983) 4551.
[8] P.E. De Jong, B.M. Brenner, From secondary to primary
prevention of progressive renal disease: the case for
screening for albuminuria, Kidney Int. 66 (2004) 21092118.
[9] P.M. Hall, Prevention of pregression in diabetic
nephropathy, Diab. Spectr. 19 (2006) 1824.
[10] K.W. Hansen, M. Mau Pedersen, C.K. Christensen, J.S.
Christiansen, C.E. Mogensen, Normoalbuminuria ensures
no reduction of renal function in Type 1 (insulin-
dependent) diabetic patients, J. Intern. Med. 232 (1992)
161167.
[11] P. Hovind, P. Rossing, L. Tarnow, U.M. Smidt, H.H. Parving,
Prog. Diab. Nephropathy 59 (2001) 702709.
[12] P. Gaede, H. Lund-Andersen, H.-H. Parving, O. Pedersen,
Effect of a multifactorial intervention on mortality in type 2
diabetes, N. Engl. J. Med. 358 (2008) 580591.
[13] P. Home, Safety of very tight blood glucose control in type 2
diabetes, Br. Med. J. 336 (2008) 458459.
[14] D.L. Jennings, J.S. Kalus, C.I. Coleman, C. Manierski, J. Yee,
Combination therapy with an ACE inhibitor and an
angiotensin receptor blocker for diabetic nephropathy: a
meta-analysis, Diab. Med. 24 (5) (2007) 486493.
[15] W.F. Keane, Z. Zhang, P.A. Lyle, M.E. Cooper, D. de Zeeuw,
J.P. Grunfeld, et al., Risk scores for predicting outcomes in
patients with type 2 diabetes and nephropathy: the
RENAAL study, Clin. J. Am. Soc. Nephrol. 1 (2006) 761767.
[16] K.P. Klausen, H. Scharling, J.S. Jensen, Very low level of
microalbuminuria is associated with increased risk of
death in subjects with cardiovascular or cerebrovascular
diseases, J. Int. Med. 260 (2006) 231237.
[17] K.P. Klausen, H. Scharling, G. Jensen, J.S. Jensen, New
denition of microalbuminuria in hypertensive subjects.
Association with incident coronary heart disease and
death, Hypertension 46 (2005) 3337.
[18] S.T. Knudsen, N.H. Andersen, C.E. Mogensen, Ambulatory
pulse pressure and progression of albuminuria in type 2
diabetes. Evidence provided. New questions emerge,
Hypertension 48 (2006) 207208.
[19] S.T. Knudsen, N.H. Andersen, S.H. Poulsen, H. Eiskjr, K.W.
Hansen, K. Helleberg, et al., Pulse pressure lowering effect
of dual blockade with Candesartan and Lisinopril vs. high-
dose ACE inhibition in hypertensive type 2 diabetic
subjects: a CALM II study post-hoc analysis, Am. J.
Hypertens. 21 (2) (2008) 172176.
[20] C.E. Mogensen, Renal Dysfunction and Hypertension, in:
B.J. Goldsten, D. Mu ller-Wieland (Eds.), Type 2 Diabetes.
Principles and Practice, Informa Healthcare, 2007.
[21] C.E. Mogensen, Prediction of clinical diabetic nephropathy
in type 1 diabetic patients: alternatives to
microalbuminuria? Messages related to the
microalbuminuria concept: 19902006, in: Robertson, R.
(Ed.), Commentaries on Perspectives in Diabetes, vol. 1
(19881992), in: R. Paul Robertson (Ed.), American Diabetes
Association 2006, 2006.
[22] C.E. Mogensen, Microalbuminuria predicts clinical
proteinuria and early mortality in maturity-onset diabetes,
N. Engl. J. Med. 310 (1984) 356360.
[23] C.E. Mogensen, C.K. Christensen, Predicting diabetic
nephropathy in insulin-dependent patients, N. Engl. J. Med.
311 (1984) 8993.
[24] C.E. Mogensen, Microalbuminuria and hypertension with
focus on type 1 and type 2 diabetes, J. Int. Med. 254 (2003)
4566.
[25] C.E. Mogensen, P.L. Poulsen, Microalbuminuria, glycemic
control, and blood pressure prediction outcome in diabetes
type 1 and type 2, Kidney Int. 66 (2004) S40S41.
[26] C.E. Mogensen, Diabetic renal disease: the quest for
normotensionand beyond, Diab. Med. 12 (1995) 756769.
[27] C.E. Mogensen, Renal function changes in diabetes,
Diabetes 26 (1976) 872879.
[28] C.E. Mogensen, Pathophysiology of diabetic complications,
Abnormal physiological processes in Kidney, in: M.
Brownlee (Ed.), Handbook of Diabetes, vol. 4, Biochemical
Pathology. Garland STPM Press, New York, London, 1981.
[29] C.E. Mogensen, Long-term antihypertensive treatment
inhibiting progression of diabetic nephropathy, Br. Med. J.
285 (1982) 685688.
[30] C.E. Mogensen, A. Chachati, C.K. Christensen, C.F. Close, T.
Deckert, E. Hommel, et al., Microalbuminuria: an early
marker of renal involvement in diabetes, Uremia Invest. 9
(1985-1986) 8595.
[31] C.E. Mogensen, A. Schmitz, C.K. Christensen, Comparative
renal pathophysiology relevant to IDDM and NIDDM
patients, Diab./Metab. Rev. 5 (1988) 453483.
[32] C.E. Mogensen, Microalbuminuria, blood pressure and
diabetic renal disease: origin and development of ideas,
Diabetologia 42 (1999) 263285.
di a b e t e s r e s e a r c h a nd c l i ni c a l p r a c t i c e 8 2 s ( 2 0 0 8 ) s 2 s 9 S8
[33] C.E. Mogensen, Microalbuminuria, renal disease, metabolic
syndrome and risks in diabetes, Diab. Metab. Syndr. Clin.
Res. Rev. 1 (2007) 127133.
[34] C.E. Mogensen, ACE-inhibitors and antihypertensive
treatment in diabetes: focus on microalbumininuria and
macrovascular disease, JRAAS 1 (2000) 234239.
[35] C.E. Mogensen, S. Neldam, I. Tikkanen, S. Oren, R. Viskoper,
R.W. Watts, M.E. Cooper, Randomised controlled trial of
dual blockade of the renin angiotensin system in
hypertensive, microalbuminuric, non-insulin dependent
diabetes: the candesartan and lisinopril microalbuminuria
(CALM) study, Br. Med. J. 321 (2000) 14401444.
[36] C.E. Mogensen, Diabetic renal and hypertensive disease, in:
H. Brunner (Ed.), The Year in Hypertension, vol. 6, Clinical
Publishing, Oxford, 2006, pp. 7383.
[37] M. Murussi, N. Campagnolo, M.O. Beck, L. Gross, S.P.
Silveiro, High-normal levels of albuminuria predict the
development of micro- and macroalbuminuria and
increased mortality in Brazilian type 2 diabetic patients: an
8-year follow-up study, Diab. Med. 24 (2007) 11361142.
[38] National Kidney Foundation: K/DOQI clinical practice
guidelines for chronic kidney disease: evaluation,
classication, and stratication, Am. J. Kidney Dis. 39 (2)
(Suppl. 1) (2002) S1S66.
[39] S. Ogawa, K. Takeuchi, T. Mori, K. Nako, Y. Tsubono, S. Ito,
Effects of monotherapy of temocapril or candesartan with
dose increments or combination therapy with both drugs
on the suppression of diabetic nephropathy, Hypertens.
Res. 30 (4) (2007) 325334.
[40] H.H. Parving, A.R. Andersen, U.M. Smidt, E. Hommel, E.R.
Mathiesen, P.A. Svendsen, Effect of antihypertensive
treatment on kidney function in diabetic nephropathy, Br.
Med. J. 294 (1987) 14431447.
[41] H.H. Parving, Jensen H, C.E. Mogensen, P.-E. Evrin,
Increased urinary albumin excretion rate in benign
essential hypertension, Lancet 1 (1974) 11901192.
[42] E. Premaratne, R.J. Macisaac, C. Tsalamandris, S.
Panagiotopoulos, T. Smith, G. Jerums, Renal hyperltration
in type 2 diabetes: effect of age-related decline in
glomerular ltration rate, Diabetologia 48 (2005) 24862493.
[43] The Heart Outcomes Prevention Evaluation Study
Investigators, Effects of an angiotensin-converting-enzyme
inhibitor, ramipril, on cardiovascular events in high-risk
patients, N. Engl. J. Med. 342 (2000) 143145.
[44] Y. Taguma, Y. Kitamoto, G. Futaki, H. Ueda, H. Monma, M.
Ishizaki, et al., Effect of captopril on heavy proteinuria in
azotemic diabetics, N. Engl. J. Med. 313 (26) (1985) 1617
1620.
[45] K.R. Tuttle, Albuminuria reduction: the holy grail for kidney
protection, Kidney Int. 72 (2007) 785786.
[46] P.J. Watkins, J.D. Blainey, D.B. Brewer, M.G. Fitzgerald, J.M.
Malins, D.J. OSullivan, et al., The natural history of diabetic
renal disease. A follow-up study of a series of renal
biopsies, Q. J. Med., New Ser., XLI 164 (1972) 437456.
[47] T.S. Kuhn, The Structure of Scientic Revolutions, 2nd
edition, The University of Chicago, 1970.
[48] P. Cortes, C.E. Mogensen (Eds.), The Diabetic Kidney,
Humana Press, Totowa, New Jersey, 2006.
[49] C.E. Mogensen (Ed.), The Kidney and Hypertension in
Diabetes Mellitus, Taylor & Francis, London, New York, 2004.
[50] C.E. Mogensen (Ed.), Pharmacotherapy of Diabetes: New
Developments, Springer, New York, 2007.
di a b e t e s r e s e a r c h a nd c l i ni c a l p r a c t i c e 8 2 s ( 2 0 0 8 ) s 2 s 9 S9