Blood pressure and metabolic control as risk factors for nephropathy in Type 1 (insulin-dependent) diabetes
Blood pressure and metabolic control as risk factors for nephropathy in Type 1 (insulin-dependent) diabetes
C h . H a s s l a c h e r 0
W. S t e c h 0
P. W a h l a n d E. R i t z 0
0 Department of Internal Medicine, University of Heidelberg , Heidelberg, FRG
Summary. The respective r61es o f arterial blood pressure and metabolic control in different stages o f diabetic nephropathy were analyzed retrospectively in 52 sequentially-followed Type 1 (insulin-dependent) diabetic patients. A negative correlation was f o u n d between median post-prandial blood glucose and median duration o f diabetes until onset o f persistent proteinuria (p<0.01). Systolic blood pressure was higher in patients who subsequently developed persistent proteinuria than those who did not (140 versus 121 m m H g ; p < 0.05), but duration o f the interval until onset o f persistent proteinuria was not related to blood pressure. After onset o f persistent proteinuria, hypertensive diabetic patients developed elevated serum creatinine concentrations more frequently than normoR e c e n t c o n c e p t s o n t h e p a t h o g e n e s i s o f d i a b e t i c nep h r o p a t h y h a v e e m p h a s i z e d t h e i m p o r t a n c e o f m e t a -
Type 1 diabetes; diabetic nephropathy; blood pres-
-
9 Springer-Verlag 1985
b o l i c c o n t r o l a n d g l o m e r u l a r h a e m o d y n a m i c s [
1-8
].
Alt h o u g h t h e r e is g e n e r a l c o n s e n s u s w i t h r e s p e c t t o t h e
r r l e o f b l o o d p r e s s u r e o n t h e c o u r s e o f o v e r t clinical n e
p h r o p a t h y , t h e r e is little a n d c o n f l i c t i n g i n f o r m a t i o n o n
t h e r61es o f b l o o d p r e s s u r e in t h e p r e - p r o t e i n u r i c stage
[
8, 9
] a n d o f m e t a b o l i c c o n t r o l i n t h e p r o t e i n u r i c s t a g e
[
10-12
], respectively.
T h e p r e s e n t r e t r o s p e c t i v e s t u d y w a s d e s i g n e d to
exa m i n e t h e s e p o i n t s . T h e r e f o r e , a g r o u p o f s y s t e m a t i c a l
l y - c o n t r o l l e d s e q u e n t i a l l y f o l l o w e d T y p e i d i a b e t i c p a t
ients w e r e e x a m i n e d to e l u c i d a t e t h e r e s p e c t i v e r61es o f
m e t a b o l i c c o n t r o l a n d b l o o d p r e s s u r e . P o s t - p r a n d i a l
b l o o d g l u c o s e a n d b l o o d p r e s s u r e at e n t r y w e r e c o m
p a r e d f o r p a t i e n t s w h o d i d a n d f o r p a t i e n t s w h o d i d n o t
d e v e l o p clinical n e p h r o p a t h y . T h e p r e d i c t i v e v a l u e o f
t h e s e f a c t o r s o n t h e clinical c o u r s e o f this c o m p l i c a t i o n
w a s assessed.
Subjects and methods
Subjects
tensive diabetic patients (67% versus 14%, p < 0.05). In these
patients, the delay until elevation o f serum creatinine
concentration
was
negatively
correlated
with
blood
glucose
(p<0.01). Once serum creatinine was raised, decay of renal
function occurred faster in patients with persistent than
intermittent hypertension (p < 0.05). No effect o f metabolic control
was demonstrable at this stage of nephropathy. It is concluded
that metabolic control determines the early course o f diabetic
nephropathy, whereas blood pressure is more important in
advanced stages of nephropathy.
sure, metabolic control.
on treatment, or when referring physicians had problems with
metabolic control. Eighty patients developed persistent proteinuria (at
least four Combur-positive urines [Boehringer Mannheim,
Mannheim FRG] during a 6-month period, protein excretion > 0.5 g/24h)
with or without elevated serum creatinine levels. The diabetic patients
with persistent proteinuria were classified as having clinical
nephropathy and were entered into the study if they fulfilled the following
criteria: (1) onset of persistent proteinuria after a total duration of
diabetes of at least 7 years and after exclusion of other renal disease by
clinical studies (bacteriological and microscopic investigation of
urine; if indicated, further examination with X-ray or ultrasound); (2)
no proteinuria at time of first visit to the outpatient clinic; (3) at least
five blood glucose and blood pressure measurements per year; (4) no
severe systemic disease, i.e. carcinoma, cardiac insufficiency, active
chronic aggressive hepatitis.
Fifty-two diabetic patients fulfilled these criteria. The median
duration of observation before the onset of persistent proteinuria was
6 years (range 2.5-11 years). Twenty-five of these patients had
intermittent proteinuria, i. e. occasional Combur-positive urines at the time
of referral. All patients had developed retinopathy (background
n = 44, proliferative n = 8) at time of onset of persistent proteinuria.
All patients with long-standing diabetes (> 20 years), who had
never had intermittent or persistent proteinuria and fulfilled criteria 3
and 4 above, were studied as a control group (n = 30). The frequency
of background retinopathy was 40% at time of entry and 65% by the
end of the study. Nine percent of the patients developed proliferative
retinopathy during the follow-up period.
Methods
Three hundred and twenty-four Type I diabetic patients (153 men,
171 women) attended the diabetic outpatient clinic of the Department
of Internal Medicine, Heidelberg, for at least 1 year between 1966 and
1983. Patients were referred either at the time o f diagnosis for advice
All patients attended the clinic at 4-8 weeks intervals. The following
measurements from the patients records were analyzed:
Blood glucose was analyzed enzymatically in capillary blood
60-90 min after breakfast.
Age at entry
to study
(years)
Age at onset
of diabetes
(years)
Time interval (years)
Proteinuria was measured in 24-h urinary collection (plastic
bottles, no preservative) with Combur test strip. Protein concentrations,
particularly albumin [
13
], can be semi-quantitatively determined in
the range between 0.3-5.0 g/1 using this test strip. Incorrect results
due to interaction with drugs, such as quinine, quinidine, penicillin
etc., could be excluded.
S e r u m ereatinine was measured at 12-month intervals in patients
with normal serum creatinine levels (55-133 txmol/1). When serum
creatinine was > 133 p~mol/1,patients were examined more frequently
(maximum of 6 months). Until 1972, a manual Jaffe method utilizing
unprocessed serum was used [
14
]; after 1972, the Technicon S M A I I C
Autoanalyzer (Technicon Corporation, Tarrytown, New York, USA)
was used; here pseudocreatinine levels were eliminated by a dialysis
step. None of the patients had acidosis at the time of serum creatinine
measurement. No elevation of serum creatinine > 133 9mol/1
occurred in any of the patients before 1972.
B l o o d pressure, systolic (phase I) and diastolic (phase V), was
measured at each visit after 5-10 min rest in the sitting position in a
separate room by one of three nurses who were working in the
outpatient clinic from 1966 to 1983. Measurements were made with a
calibrated standard mercury manometer, the accuracy of which was
controlled at 12-month intervals. The bladder width was 12 cm.
Body weight was recorded as body mass index (kg/m 2) using a
standard balance with light indoor clothing, but no shoes.
Metabolic control and anti-hypertensive therapy
Advice as to diet and insulin was given by one of the two physicians
who were involved in patient care throughout the study period. Eighty
percent of patients were given two injections of insulin per day. The
remainder injected insulin either once (14%) or several times per day
(6%). For treatment surfen (Hoechst) or protamine-containing
insulins were normally used. During the last 6-8 years of the observation
period, home monitoring of glucose was carded out by most patients
[56% blood glucose with Haemo-Glukotest 20-800 (Boehringer
Mannheim, Mannheim, FRG) or Dextrostix (Ames, Frankfurt,
FRG); 25% urine glucose control using Glukotest (Boehringer
Mannheim, Mannheim, FRG) and 19% no self-control].
For treatment of blood pressure in the early 1970s diuretics,
reserpine and a-methyldopa were normally used; thereafter, diuretics were
usually combined with a- and t-receptor blocking agents. None of the
treated hypertensive patients was normotensive throughout the
observation period. Only 18% of these were taught to measure their own
blood pressure. Five patients had taken oral contraceptives, but none
was hypertensive.
Classification of blood pressure
Established hypertension was defined according to modified World
Health Organisation criteria, when at least two measurements per
year were > 160 mmHg systolic and/or > 95 mmHg diastolic a n d / o r
when the patient required anti-hypertensive medication. The
hypertensive status of patients was classified as: no hypertension: blood
pressure always ~<160/~< 95 mmHg, intermittent hypertension: blood
pressure repeatedly, but not constantly > 1 6 0 / > 95 mmHg; persistent
hypertension: blood pressure continuously > 1 6 0 / > 9 5 m m H g .
Correlations were calculated using the overall medians of systolic and
diastolic pressures, respectively.
Termination of observationperiod
Patient follow-up ended because of death, initiation of dialysis or loss
to follow-up when patients moved away. For those patients
continuing in the outpatient clinic, observation ended on 31 December 1983.
At that time, 20 with clinical nephropathy and 16 without were still
being followed in the outpatient clinic. Fourteen of the 52 diabetic
patients developed persistent proteinuria, but none of those without
died during the observation period. Causes of death according to
clinical diagnosis were: renal failure (4), coronary heart disease (3),
cerebrovascular accident (3), sepsis (1), unknown (3). Three are currently
on maintenance haemodialysis. Twelve with clinical nephropathy and
10 without have moved away.
Statistical analysis
All values are given as median and range. Differences between groups
were tested with Wilcoxon's test or zZ-test as indicated. Linear
regression analysis was used to calculate correlations.
Results
The patient's characteristics at the time of entry into the
study are described in Table 1. Diabetic patients who
subsequently developed nephropathy did not differ
significantly from those who did not with respect to sex,
age, age at onset of diabetes, median duration of
diabetes at entry into the study or duration of follow-up.
Body weight did not change significantly during the
observation period.
In patients with subsequent nephropathy, persistent
proteinuria was present after a median duration of
19 years (range 10-30years) and serum creatinine
increased in 25 of these after a median duration of
diabetes of 22 years (range 11-42 years). The time of onset of
persistent proteinuria seems to be bimodally distributed
with one peak at 14/15years and a second peak at
22/23 years after diagnosis of diabetes (Fig. 1). In men,
14 developed proteinuria before and eight after 20 years
of diabetes. In women, however, 15 developed
proteinuria before and 15 after 20 years of diabetes.
The median post-prandial glucose concentrations
during the first 6 years of observation were significantly
higher in patients who did subsequently develop
persistent proteinuria than those who did not - 11.5
mmol/1 (range 7.9-15.5mmol/1) versus 10.1mmol/1
(range 7.2-14.5 mmol/1) respectively (p<0.05). Again,
in the patients who subsequently developed
nephropathy, a higher median systolic blood pressure was
detected during the pre-proteinuric stage than in the control
subjects - 140 m m H g (range 115-196 mmHg) versus
121 m m H g (range 105-168 mmHg) respectively
( p < 0.05). Diastolic blood pressure was not different.
The prevalence of established hypertension was 44% in
the patients with subsequent persistent proteinuria and
7% in those without ( p < 0.05). The differences between
the two groups in median blood glucose, median blood
pressure and prevalence of established hypertension
remained significant, even when 25 patients of the group
with subsequent nephropathy, referred at the stage of
intermittent proteinuria, were omitted.
There was a striking increase in the prevalence of
hypertension and in median blood pressure as
nephropathy progressed; at the time of persistent proteinuria the
prevalence of hypertension was 67%, median blood
pressure 148/88mmHg, median age 43years (range
20-69 years). Corresponding data at time of increase
of serum creatinine > 133 ~tmol/1 were 92%,
158/92 m m H g and 45 years (range 22-69 years)
respectively. In contrast, metabolic control did not change
substantially throughout the observation period (data
not shown).
:
9
9
9
~ ~ . ~ . ~
Time interva/ (years)
In patients who did not develop nephropathy, the
prevalence of hypertension increased only to 17% and
median blood pressure to 132/81 m m H g by the end o f
the observation period. There was also no substantial
change in metabolic control during follow-up. At the
end o f the observation time, these patients had a
median age of 45 years (range 26-47 years) and a median
duration of diabetes of 24 years (range 20-31 years).
Effect of metabolic control and blood pressure on onset of persistent proteinuria
Among the diabetic patients who developed
nephropathy, a negative correlation has been found between the
median blood glucose levels and the time interval
between diagnosis of diabetes and onset of persistent
proteinuria (Fig. 2). This result cannot be explained by
differences of blood pressure, since no correlation could
be found between median blood glucose levels and
median blood pressure. In contrast, blood pressure status
had no predictive value with respect to the time interval
between diagnosis and onset of persistent proteinuria
(Table 2). Further sub-classification of normotensive
patients, e.g. into median systolic blood pressure
< 130 m m H g ( n = 10) or > 130 m m H g ( n = 12) similarly
revealed no significant difference. There were no
significant differences in post-prandial glucose levels
between the three blood pressure groups.
Effect of rnetabolic control and blood pressure on course of persistent proteinuria
Four o f the 52patients who developed clinical
nephropathy reached an endpoint of the study at the time
of onset of persistent proteinuria (death 1, moving away
3). The remainder (n = 48) were followed until elevation
of serum creatinine, drop-out or the end of the study. In
25 serum creatinine rose above 133 ~tmol/1 and in 23 no
increase was observed during the follow-up period
(median 3 years, range 1-13 years) in each group. The sex
ratio, age and onset o f nephropathy were similar in
these two groups (Table 3). However, in patients who
subsequently developed elevated serum creatinine,
persistent hypertension was more prevalent (40% versus
8%) and median systolic blood pressure was higher
(p < 0.01). Diastolic blood pressure was not significantly
different. No correlation was found between systolic
blood pressure and the time interval between onset of
persistent proteinuria and elevation of serum creatinine.
Blood glucose levels at the time of proteinuria were
not significantly different in patients whose serum
creatinine rose and those who did not (0.05<p<0.1).
However, in patients who developed renal failure, a
correlation was found between the glucose levels at the
time of proteinuria and the time interval between onset
of persistent proteinuria and elevation of serum
creatinine ( r = 0.53, p < 0.01 ; Fig. 3). A similar correlation was
found for the median of all post-prandial blood glucose
values since entry into the study ( r = 0.6t, p < 0.001).
Effect o f metabolic control and blood pressure on the course of renal failure
Nine of the 25 patients who developed elevation of
serum creatinine reached an endpoint of the study within
a maximum of 4 months after the first increase of serum
creatinine (death 2, moving away 2, end of observation
5). The remainder (n=-16) were followed for a median
of 29 months (range 9-73 months) after serum
creatinine had risen above 133 ~tmol/1. Eight diabetic patients
(3 men, 5women; median age 47 years, range
25-69years) had intermittent hypertension, eight
(4 men, 4women; median age 45 years, range
22-65 years) had persistent hypertension. Renal
function, indicated by the reciprocal of serum creatinine
versus time, decayed faster in patients with persistent
compared with intermittent hypertension, but no correlation
was found between the slope of the reciprocal of serum
creatinine versus time and systolic or diastolic blood
pressure, respectively (Fig. 4). No correlation could be
detected between concurrent blood glucose levels and
decay of renal function.
Discussion
The main problems of retrospective studies are the
possibilities of sampling error and of diagnostic criteria
changing with time. In the present study all consecutive
patients fulfilling the entry criteria were entered and the
technique used for patient examination remained
reasonably standardized throughout the observation
period. Quantitative measurements of urinary protein
excretion, and of HbAI, however, were not performed
during the whole study period. One theoretical
shortcoming of the study is the fact that anti-hypertensive
therapy was introduced as a confounding variable.
However, only a minority of patients had their blood
pressure effectively controlled despite the prescription
of such medication. The conclusions drawn from our
observations concern actual blood pressure, irrespective
of whether or not the patient was on medication. These
blood pressure levels in treated patients represent the
perfusion pressures to which the kidneys are exposed.
The present study shows that pre-proteinuric Type 1
diabetic patients who subsequently developed clinical
nephropathy have a slight, but significant, elevation of
systolic blood pressure and a higher prevalence of
established hypertension compared with long-standing
Type 1 diabetic patients without subsequent
nephropathy. These results are in agreement with previously
published studies [
9, 15, 16
] which have found elevated
blood pressure levels in diabetic patients with
microalbuminuria. Although the difference of systolic blood
pressure was not great in magnitude, this observation
may be of interest with respect to the findings of
Knowler et al. [
15
]. They noted that diabetic Pima Indians
with low normal blood pressure developed less retinal
damage than individuals with upper normal blood
pressure (<125 versus 125-145 mmHg systolic). However,
in the present study, blood pressure did not influence
the time interval between the onset of diabetes and the
onset of proteinuria. Furthermore, an effect of blood
pressure on even earlier stages of nephropathy (i. e.
incipient nephropathy) could not be detected recently [
16
].
Ch. Hasslacheret al.: Riskfactorsfor nephropathyin TypeI diabetes
These findings suggest that a rise in blood pressure in
pre-proteinuric diabetic patients is not of major
pathogenic importance for the onset of clinical nephropathy.
In agreement with previous suggestions [
6-8
], we
noted that metabolic control had a considerable
influence on the time interval between onset of disease and
onset of proteinuria. However, if one compares patients
who never developed proteinuria and those who did,
considerable overlap of the median blood glucose levels
is apparent. Both in patients who subsequently became
proteinuric and those who did not, no correlation was
found between blood pressure and the quality of
metabolic control. This indicates that it is presumably not
low blood pressure which protects some
poorly-controlled diabetic patients from developing proteinuria.
Like Anderson et al. [
18
] we were able to show two
frequency peaks for the onset of persistent proteinuria. In
addition, the onset of clinical nephropathy seems to be
earlier in males. This might indicate a
genetically-determined heterogeneity of diabetic nephropathy.
Our data on patients with persistent proteinuria
confirm the previous observations of Mogensen et al. [
2
]
and Parving et al. [
3
] that blood pressure is a major
determinant of the course of clinically overt nephropathy.
Fourteen percent of normotensive, but 67% of
hypertensive patients with proteinuria developed renal
failure, i.e. elevated serum creatinine, during a median
observation period after the onset of proteinuria of 3 years.
The influence of hypertension was also striking after
serum creatinine had risen above normal, since decay of
renal function was related to blood pressure status.
However, as in other studies [
19-21
], we were unable to
detect a relationship between systolic or diastolic blood
pressure values, on the one hand, and the time interval
between onset of persistent proteinuria and increase of
serum creatinine or the slope of decay of renal function,
on the other. As discussed by others [
21
], this may be
due to the fact that only a minority of our hypertensive
patients had diastolic blood pressure > 1 0 0 m m H g .
Such high diastolic pressures seem to be largely
responsible for the correlation between blood pressure and the
fall of glomerular filtration rate described by Mogensen
[
1
]. Blood glucose levels at the time of persistent
proteinuria did not predict the risk of developing renal
failure because no striking difference of metabolic control
could be detected between patients who went into renal
failure and those who did not (Table 3). However, in the
patients whose serum creatinine rose above normal, a
significant correlation was noted between blood
glucose levels (before and after onset of persistent
proteinuria) and the time interval between onset of proteinuria
and onset of renal failure. The results are compatible
with the notion that metabolic control continues to
influence the course of nephropathy even after persistent
proteinuria had developed [
11
]. So far only Viberti et al.
[
12
] have failed to find an effect of near-normalisation
of metabolic control by insulin pump therapy on the
further decay of renal function in a small group of
diabetic patients with proteinuria (n = 3). Only when serum
creatinine has risen above normal can no further
influence o f metabolic control on the course o f nephropathy
be established. These findings are in agreement with the
observation o f other groups [
10, 12
] that further
deterioration o f renal function in such patients cannot thus be
prevented, even b y near-normalisation o f metabolic
control.
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3. Parving HH , Andersen AR , Smidt UM , Svendsen PA ( 1983 ) Early aggressive anti-hypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy . Lancet 1 : 1175 - 1179
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Received: 4 May 1984
and in revised form: 11 October 1984