Circadian rhythm of arterial blood pressure and albuminuria in diabetic nephropathy

Kidney International, Vol. 50 (1996), pp. 579 —585

Circadian rhythm of arterial blood pressure and albuminuria in diabetic nephropathy HENRIK P. HANSEN, PETER RossING, UsE TARNOW, FLEMMING S. NIELSEN, BERIT R. JENSEN, and HANS-HENRIK PARVING Steno Diabetes Center, DK-2820 Gentofte, Denmark

Circadian rhythm of arterial blood pressure and albuminuria in diabetic nephropathy. The aim of our study was to evaluate the diurnal relationship between arterial blood pressure and albuminuria, and some potential mechanisms responsible for impaired nocturnal blood pressure reduction (non-dippers, groups I and II) in diabetic nephropathy (DN). Twenty-four-hour ambulatory blood pressure, heart rate (HR) variation (autonomic nervous function) and extracellular fluid volume (ECV) were

measured, and urine samples were collected three times during the corresponding day- and nighttimes in 47 insulin-dependent diabetic (IDDM) patients with DN. Mean arterial blood pressure (MABP) during

the daytime [mm Hg, median (range)I was identical in group I 105 (96—137)1, group II [109 (86—124)1 and group III [dippers; average blood pressure reduction from day to night> 10%, 107 (93—132), P = NS], while

the nighttime MABP differed [group I, 106 (95—144); group II, 100 (78—118); group III, 91(76—118); P < 0.001]. No significant difference

between the groups concerning the daytime or nighttime albuminuria

[Lg/min; median (range)] was observed; [Day: group 1, 1467 (235—3933); group II, 695 (170—6719); group III, 875 (228—3173). Night: group I, 1079

[1, 7—9]. These changes may induce a blunted nocturnal reduction in albuminuria, particularly in patients with impaired renal auto-

regulation, as demonstrated in IDDM patients with diabetic nephropathy [10]. Autonomic dysfunction has been suggested to play a role in the genesis of blunted nocturnal reduction in arterial blood pressure [11 and in urinary albumin excretion rate in IDDM patients without nephropathy [11]. The pathophysiological factors leading to blunted nocturnal arterial blood pressure reduction are likely to be multifactorial, as suggested by the recent finding that latent fluid retention may contribute to nocturnal hypertension in diabetic nephropathy [121. Our study aimed to elucidate a possible relationship between day to night changes in arterial blood pressure and day to night changes in the urinary albumin excretion rate, and to examine some potential mechanisms responsible for the impaired noctur-

(279—4665); group II, 572 (113—3807); group III, 659 (81—2493)]. A significant correlation between MABP and albuminuria was demonstrated during day- (p = 0.50, P < 0.0005) and nighttime (p = 0.46, P < 0.005), while neither the absolute nor the relative changes in MABP from day to night correlated significantly with absolute or relative changes in albuminuria from day to night. The night/day ratio of HR was higher in group I [0.93 (0.76—1.09), median (range)] compared to group III [0.83 (0.74— 1.02), P < 0.005] and a significant correlation between this ratio and the night/day ratio of MABP was found (p = 0.54, P < 0.0005). ECV was about the same in the three groups. Our study indicated an association between blood pressure and albuminuria, but the mechanisms involved in

nal arterial blood pressure reduction in IDDM patients with

the reduction of albuminuria from day to night was not unraveled. A relative lack of sympathetic withdrawal during sleep seems to be an

ular filtration rate (GFR) 25 ml min1 .

diabetic nephropathy. Methods Patients Forty-seven consecutive IDDM patients with diabetic nephropathy, who fulfilled the following inclusion criteria were enrolled in the present study: persistent albuminuria > 300 mg/24 hr, glomer-

1.73 m2, an average of three or more consecutive diastolic blood pressure readings 105 mm Hg, without antihypertensive treatment (except furosemide, N = 10), and age between 18 to 55 years. Patients were excluded if they had a previous history of stroke and/or transient Diurnal variations in arterial blood pressure and urinary albu- ischemic attacks, congestive heart failure (NYHA III-IV), myomin excretion rate are present in normal subjects and patients cardial infarction or coronary bypass surgery within the last three with diabetic or non-diabetic glomerulopathies [1—6]. The normal months, and/or an unstable angina pectoris. All patients had been reduction from day to night varies between 10 to 30% in arterial insulin-dependent from the time of diagnosis and all were receivblood pressure and between 20 to 40% for the urinary albumin ing at least two daily injections of insulin. Diabetic nephropathy excretion rate. Recent studies have demonstrated that insulin- was diagnosed clinically if the following criteria were fulfilled: dependent diabetic (IDDM) and non-insulin-dependent diabetic persistent albuminuria above 300 mg/24 hr, presence of diabetic (NIDDM) patients suffering from diabetic nephropathy fre- retinopathy and no clinical or laboratory evidence of other kidney quently have blunted nocturnal arterial blood pressure reduction or renal tract disease, other than diabetic glomerulosclerosis [13].

important feature of nocturnal hypertension in diabetic nephropathy.

Diabetic retinopathy was evaluated by fundus photography (Can-

on CFD-602, Kawasaki, Japan) after pupillary dilatation and Received for publication October 18, 1995 and in revised form January 22, 1996 Accepted for publication February 20, 1996

© 1996 by the International Society of Nephrology

graded as none, simplex or proliferative. Thirty-five patients had

received antihypertensive treatment for at least two years; 26 patients were treated with an angiotensin converting enzyme inhibitor (ACE!) either alone (N = 7) or in combination with one

579

580

Hansen et al: BP and albuminuria in diabetic nephropathy

or more conventional antihypertensive drugs (diuretics, calcium 3.7 MBq 5Cr-labeled eidetic acid (51Cr-EDTA) at 8 a.m., by channel blockers, selective /3-blockers, a-blockers). Nine patients determining the radioactivity in venous blood samples 180, 200, were treated with conventional antihypertensive drugs (see 220 and 240 minutes after the injection [24, 25]. Extracellular fluid above). Three newly diagnosed hypertensive patients did not volume was determined to be the distribution volume of 51Crreceive antihypertensive treatment. Nine patients were normoten- EDTA [26]. The results were standardized for 1.73 m2 body sive. Patients were divided according to the nocturnal reduction in surface area. The mean intra-individual coefficient of variation of arterial blood pressure in non-dippers (groups I and II) and the glomerular filtration rate and extracellular fluid volume from dippers (group III). Non-dippers were defined as subjects with an day to day is 4% and 15%, respectively, in our laboratory. Body average reduction in systolic and diastolic blood pressure from mass index (BMI) was calculated as weight (kg) height (m)2. day to night of 10% [14]. The non-dippers were furthermore From venous blood samples hemoglobin A1 (HbA1) was meadivided into two groups, group I below and group II above the sured by high-performance liquid chromatography (DIAMAT median. All patients participating in the study were Caucasians, analyzer; Bio-Rad, CA, USA). The normal range of HbA1C in our and all gave informed consent to participate in the study. The laboratory is 4.1 to 6.4%. study was approved by the Regional Ethics Committee. Statistical analysis

Methods If treatment was given, all antihypertensive drugs were with-

All data are expressed as median (range), except when indicated. The Mann-Whitney U-test and the Kruskal-Wallis test of drawn four weeks before examination, except in ten patients variance was used to test for differences between two and three receiving furosemide because of overt edemata. Three consecu- groups, respectively. The Wilcoxon signed-ranks test was used to tive 24-hour urine samples were collected. They were all divided test paired data. For each patient the night and day urinary into day- and nighttime portions according to the actual bed albumin excretion rates and the urinary sodium excretion rate are times. The content of urinary albumin and sodium were measured expressed as the median of three night and day collections, by using an enzyme-linked immunoadsorbent assay [151 and a respectively. Correspondingly, the night/day ratios of the urinary flame photometric method (Flame photometer FLM 3; Radiom- albumin excretion rate and urinary sodium excretion rate for each eter, Copenhagen, Denmark), respectively. Twenty-four-hour am- patient are represented as the median of three night/day ratios. bulatory blood pressure was measured simultaneously with the The chi-square test was used for evaluating frequencies. Spearthird 24-hour urine collection, at the homes of the patients, with man's rank correlation coefficient was used for correlations, a Takeda TM2420 device version 6 or 7 (A&D, Tokyo, Japan) except when indicated. All calculations were made using Stat[16—18]. A cuff size of 20 to 31 cm was used in patients with an graphics (STSC; Rockville, MD, USA). A P value of < 0.05 was arm circumference less than 32 cm and a cuff size of 28 to 36 cm considered significant (two-tailed). was used in patients with an arm circumference above 32 cm. Results Blood pressures and heart rates were measured every 15 minutes The three groups with different nocturnal arterial blood presduring the daytime (0700 to 2300 hours) and every 30 minutes during the nighttime (2300 to 0700 hours) [19]. Twenty-four-hour sure reduction were similar with respect to the following: sex ratio, blood pressure measurements were accepted if at least 50% of the age, duration of diabetes, HbAIC, BMI, insulin dosage, duration of programmed pressures were measured successfully for each hour diabetic nephropathy and level of retinopathy (Table 1). Further-

during the whole 24-hour monitoring interval. No editing was more, the nine normotensive patients were equally distributed performed in the recorded blood presure values. Values were among the three groups. There was a significant decline in MABP from 107 (86—137) averaged for each hour before calculating day, night and 24-hour blood pressure. The mean arterial blood pressure was calculated mm Hg during daytime to 100 (76—144) mm Hg during nighttime as one-third of the difference betwr .n systolic and diastolic blood (P < 0.0001) in the whole group of patients. A similar diurnal pattern was observed in albuminuria: 1123 (170—6719) jsg min1 pressure plus the diastolic blood pressure. The between visits coefficient of variation for ambulatory blood (daytime) versus 841 (81—4665) jsg min1 (nighttime) (P < pressure (ABP) monitoring for systolic blood pressure was: 24- 0.0001). The median glomerular filtration rate was 82 (32—139) ml hour 6%, daytime 6%, nighttime 7%; for diastolic blood pressure min1 1.73 m2 and the median extracellular fluid volume was 14.0 (11.0 —18.5) liters• 1.73 m2. Table 2 illustrates the results in the ABP was: 24-hour 8%, daytime 11%, and nighttime 10%. Cardiac autonomic nervous function (primarily parasympa- the three groups of patients. Daytime MABP and 24-hour MABP thetic) was assessed by the beat-to-beat variation during deep values were alike in the three groups. The daytime heart rate breathing [< 4 beats min (abolished), 5 to 15 beats min1 (HR) was comparable in the three groups, while the nighttime (impaired) and > 15 beats min1 (normal)] [20, 21]. The HR tended to be highest in group I and lowest in group III, with coefficient of variation for beat-to-beat variation during deep group II in-between (P = 0.09). The night/day ratio of HR was breathing is 24% in our laboratory. As an overall indicator, mainly higher in group I compared to group III (P < 0.005). Furtherof cardiac and neurohumeral sympathetic activity, we determined more, we found a correlation between the night/day ratio of HR the night/day ratio of heart rate [22, 23]. Determination of the and the night/day ratio of arterial blood pressure (p = 0.54, P < GFR and extracellular fluid volume (ECV) were performed with 0.0005; Fig. 1). Group I, completely lacking nocturnal blood the patients in the supine position between 8 a.m and 1 p.m., after pressure reduction, tended to have the highest albumin excretion an overnight fast. Patients had breakfast and morning insulin 30 rate both during night- and daytimes (P < 0.15, comparing group minutes after the start of the investigation, and drank approxi- I vs. group III). No significant differences were found in the ratio mately 200 ml of tap water per hour during the investigation of night to day urinary excretion rates of albuminuria and sodium period. GFR was measured after a single intravenous injection of between the three groups. Glomerular filtration rate, extracellular

581

Hansen et al: BP and albuminuria in diabetic nephropathy Table 1. Clinical characteristics of 47 IDDM patients with diabetic nephropathy

Group I

Group II

Group III

N=16

P

7/9

5/10

37 (2 1—53)

39 (26—59) 23 (16—39) 9.7 (7.0—10.8) 25.2 (19.8—32.6) 0.64 (0.42—0.96)

5/11 39 (28—55) 22 (14—34) 8.8 (6.5—11.3) 24.9 (19.7—30.1)

NS NS NS NS NS NS

N=16

Sex (F/M) Age years Duration of diabetes years HbA1, %

Body mass index kg m2

Insulin dosage U kg' day'

Duration of persistent albuminuria years Retinopathy (simplex/proliferative) No. of patients receiving furosemidea Furosemide dose mg daily'

24 (15—46) 9.4 (8.1—12.2) 24.8 (19.5—37.1) 0.64 (0.44—1.24) 6 (1—19)

N=15

6 (4-12)

4/12 3 240 (200—500)

5/10 2 395 (40—750)

0.65 (0.34—0.89) 6 (2—15)

NS

9/7

NS

5 80 (40—1000)

NS NS

Data are median (range). Patients are divided according to the nocturnal reduction in arterial blood pressure in non-dippers (group I and II) and dippers (group III). Non-dippers are defined as subjects with an average reduction in systolic and diastolic blood pressure from day to night of 10%. The non-dippers are furthermore divided into two groups, group I below and group II above the median. a At time of investigation b Only patients receiving furosemide

Table 2. Mean arterial blood pressure (MABP), mean heart rate (HR), albuminuria (UAE), urinary sodium excretion rate (UNaE), glomerular filtration rate (GFR), extracellular fluid volume (ECV), and cardiac autonomic nervous function (beat-to-beat) in 47 IDDM patients with diabetic nephropathy Group I

N=16 24-Hour MABP mm Hg Nighttime MABP mm Hg Daytime MABP mm Hg Night/day MABP

24-Hour HR beats min' Nighttime HR beats min' Daytime HR beats min1 Night/day HR 24-Hour UAE mg

Nighttime UAE pg min' Daytime UAE pg min' Night/day UAE

Nighttime UNaE pmol min' Daytime UNaE pinol min' Night/day UNaE

GFR m1 min' 1.73 m2 ECV 1iter 1.73 m2 ECV % of bodyweight

Beat-to-beat beats min1

105 (96—140) 106 (95—144) 105 (96—137) 1.00 (0.95—1.18) 87 (65—103) 83 (55—98) 88 (71—106) 0.93 (0.76—1.09) 1980 (394—5485) 1079 (279—4665) 1467 (235—3933) 0.78 (0.51—1.99) 139 (32—269) 91 (28—191) 1.33 (0.43—3.65) 86(49—121) 13.4 (11.8—18.5) 19.5 (16.5—26.9) 5 (0—25)

Group II

N=15

107 (83—122)

100 (78—118) 109 (86—124) 0.92 (0.90—0.95) 86 (74—95) 80 (66—91) 90 (77—98) 0.90 (0.76—1.00) 868 (238—7716) 572 (113—3807) 695 (170—6719) 0.63 (0.19—1.56) 147 (25—253) 127 (53—357) 0.79 (0.21—2.64)

74(40—124) 13.5 (11.8—18.0) 20.9 (15.1—27.5) 6 (2—16)

Group III

N=16

P

102 (89—128) 91(76—118) 107 (93—132) 0.84 (0.75—0.89) 84 (66—99) 74 (53—87) 89 (72—106) 0.83 (0.74—1.02) 1231 (297—4149) 659 (81—2493) 875 (228—3173) 0.70 (0.35—2.83) 107 (43—417) 130 (41—244) 0.88 (0.19—4.01) 95 (32—139) 14.3 (11.0—16.8) 21.0 (17.4—24.7) 7 (1—15)

NS <0.00051,c NS <00001a,b,c NS

0.09 NS <0.005c NS NS NS NS NS NS NS NS NS NS NS

Data are median (range). Patients are divided according to the nocturnal reduction in arterial blood pressure in non-dippers (group I and II) and dippers (group III). 10%. The non-dippers Non-dippers are defined as subjects with an average reduction in systolic and diastolic blood pressure from day to night of are furthermore divided into two groups, group I below and group II above the median. a Between group I—Il h Between group Il—Ill Between group I—Ill

fluid volume and beat-to-beat variation during deep breathing were about the same in all three groups. Significant correlations between daytime MABP and daytime albuminuria (p = 0.52, P < 0.0005; Fig. 2), between nighttime MABP and nighttime albuminuria (p = 0.46, P < 0.005; Fig. 2), and between 24-hour MABP and 24-hour albuminuria (p 0.57, P < 0.0005) were found. No significant correlations between the night/day ratio of MABP and night/day ratio of albuminuria (p = 0.02, P

(daytime albuminuria) and night/day ratio of MABP (r = 0.08,

P = 0.59, linear regression) were found.

The 47 patients were divided into two groups according to the

median value of ECV (14.0 liter 1.73 m2). One group of patients had an ECV below the median and another group of patients an ECV above the median. Clinical and laboratory characteristics of the two groups were comparable, except the extracellular fluid volume (Table 3). In both groups there was a

= 0.89; Fig. 3), between nighttime MABP minus daytime significant reduction in systolic and diastolic blood pressure from

MABP and nighttime albuminuria minus daytime albuminuria (p day to night of 5%/5% in patients with an ECV below the median = —0.14, P = 0.35), or between log (nighttime albuminuria)/log and 8%/9% in patients with an ECV above, respectively. The

582

Hansen et al: BP and albuminuria in diabetic nephropathy

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70 80 90 100 110 120 130 140 150

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Night/day ratio of heart rate Fig. 1. Correlation between the variation in night to day heart rate and variation in night to day mean arterial blood pressure (MABP) (rho = P < 0.0005) in 47 IDDM patients with diabetic nephropathy.

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night/day ratio of systolic and diastolic blood pressure was not 70 80 90 100 110 120 130 140 150 significantly different between the two groups (Table 3). The degree of nocturnal reduction in arterial blood pressure was Nighttime MABP, mm Hg normally distributed in both groups. The difference in nocturnal 2. A. Correlation between daytime mean arterial blood pressure Fig. arterial blood pressure reduction between patients with an ECV (MABP) and daytime albuminuria (p = 0.52, P < 0.0005). B. Correlation below and above the median, was —3.4% with a 95% confidence between nighttime mean arterial blood pressure (MABP) and albuminuria interval from —8.5 to 1.7%. The urinary sodium excretion rate (p = 0.46, p < 0.005) in 47 IDDM patients with diabetic nephropathy. tended to be lower in patients with an ECV below the median compared with patients with an ECV above (P < 0.06) during 2.5 daytime, but was the same during nighttime (Table 3). Omitting the ten patients treated with furosemide had no significant impact C 2 E on the variables presented in Table 3.

. . .0

Discussion

Our cross-sectional study in IDDM patients with diabetic

0 0

nephropathy revealed an impaired nocturnal arterial blood pres-

sure reduction in the majority of the patients, a relationship between arterial blood pressure and albuminuria during the day and night measurements, and a lack of association between the absolute or relative degree of nocturnal arterial blood pressure reduction and the absolute or relative degree of nocturnal reduction in albuminuria. Our study suggests that impaired cardiac autonomic nervous function (mainly lack of sympathetic withdrawal) during sleep is an important feature of nocturnal hypertension in IDDM patients with diabetic nephropathy and wellpreserved kidney function. Extracellular fluid retention was not related significantly to the presence or absence of arterial blood pressure dipping. The diurnal rhythmicity of albuminuria depends on alterations in the filtered load and/or tubular reabsorption of albumin. A major increase in tubular protein reabsorption from day to night is highly unlikely, since the protein reabsorption capacity is fully

saturated in protenuric patients. Furthermore, the observed

>,

1.5

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U

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0.5

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0.7

0.8

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I

I

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0.9

1

1.1

1.2

Night/day ratio of MABP Fig. 3. Lack of correlation between variation in night to day mean arterial blood

pressure (MABP) and variation in night to day albuminuria (rho = 0.02; p

=

0.89).

changes in the urinary /32-microglobulin excretion rate in nephro-

pathic patients cannot account for the circadian rhythm of proteinuria [27]. The filtered load of albumin depends on serum albumin concentration, the size and charge selective properties of

Hansen et al: BP and albuminuria in diabetic nephropathy Table 3. Clinical and laboratory characteristics of 47 IDDM patients

with diabetic nephropathy, divided into two groups, according to the median value of ECV Below the median

N=23

N=24

P

6/18

NS NS NS NS NS NS

40 (2 1—59)

38 (28—5 3)

24(15—46)

23(14—36)

HbA1C %

9.7 (6.7—1 2.2)

9.3 (6.5—10.9)

11/12

Body mass index kg m2 24.7 (19.5—32.6) 25.2 (20.8—37.1) Insulin dosage

Ukg' day1

Duration of persistent albuminuria years Nighttime albuminuria

pg min'

Daytime albuminuria

0.67 (0.34—1.24) 0.62 (0.42—0.89) 6 (1—17)

6 (2—19)

801 (110—2800) 1102 (81—4665)

NS

141 (104—203)

NS

153 (133—193r

163 (115_187)a

NS

0.95 (0.74—1.30) 0.92 (0.71—1.10)

NS

76 (65—1 13)

80 (57—117)

NS

82 (74_98)C

87 (69—112)

NS

140 (25—417)

121 (32—289)

NS

Daytime UNaE

117 (28—174)"

138 (41—357)"

<0.06

UNaE night/day ratio Glomerular filtration

1.21 (0.21—3.65) 0.88 (0.19—4.01)

pmolmin'

rate mlmin'

86 (32—124)

79 (40—1 39)

NS NS

1.73 m2

Extracellular fluid volume liter . 1.73 m2 Extracellular fluid

19.2 (15.1—22.9) 21.5 (17.8—27.5) <0.001

body weight

beats mm

'

No. of patients receiving furosemide' Furosemide dose mg daily2

5 (1—25)

7 (0—22)

non-diabetic animals with various experimental glomerulopathies

[36]. Conversely, acute and chronic reduction in P0 lowers urinary albumin excretion [37]. We have previously demonstrated

because of changes in the ratio of the afferent/efferent arteriolar resistance, or that other non-hemodynamic determinants of albuminuria offset the reducing effect of blood pressure lowering. It

should be mentioned that the circadian rhythm of GFR is not determined by the circadian variation of MABP in diabetic patients (B.A.C. van Acker, personal communication). However,

13.1 (11.0—14.0) 14.8 (14.0—18.5)

volume % of Beat-in-to-beat

Increased glomerular capillary hydraulic pressure (PGC) en-

hances the transglomerular albumin passage in diabetic and

This finding suggests that either the arterial blood pressure reduction was not transmitted to the glomerular capillaries,

140 (100—214)

Nighttime UNaE

pinol min'

nephrons with different protein permeability as suggested by Arisz [35] may contribute to the circadian rhythmicity in albuminuria, if present in diabetic nephropathy.

NS

NS

1043 (170—3173) 1475 (174—6719) NS

0.95 (0.76—1.15) 0.91 (0.75—1.06)

(fractional clearance of IgG/transferrin) [2, 3], the ratio being

that acute reduction in arterial blood pressure reduces albuminuria and GFR in IDDM patients suffering from diabetic nephropathy [101. Recently we found a relationship between chronic changes in MABP and changes in both albuminuria and GFR in diabetic nephropathy [38]. The previous demonstration of impaired or in some cases even completely abolished autoregulation of GFR (and probably also PGC) may aggravate the impact of reduction in MABP on glomerular hemodynamics. Even though our study revealed a correlation between MABP and albuminuria both during day- and nighttime, as reported recently by Mulec et a! [12], no relationship was demonstrated between the variation from day to night in MABP and albuminuria. Patients with a blunted nocturnal decline in MABP (non-dippers) had the same degree of day to night reduction in albuminuria as did the dippers.

pg• min'

Nighttime systolic blood pressure mm Hg Daytime systolic blood pressure mm Hg Night/day ratio of systolic blood pressure Nighttime diastolic blood pressure mm Hg Daytime diastolic blood pressure mm Hg Night/day ratio of diastolic blood pressure

in diabetic glomerulopathy, while some patients with non-diabetic glomerulopathies have a diurnal variation in the selectivity index

lowest during nighttime. A redistribution of blood flow to

Above the median

Sex (F/M) Age years Duration of diabetes years

583

NS

4

6

NS

140 (40—250)

350 (40—1000)

NS

Data are median (range). up < 0.01 compared to nighttime blood pressure b NS compared to nighttime urinary sodium excretion rate (UNaE) C At time of investigation Only patients receiving furosemide

the diurnal variation in GFR will tend to reduce the circadian variation in fractional albumin clearance (albuminuria GFR' serum albumin concentration'). Twenty-four-hour blood pressure and heart rate measurements have shown a circadian variation, characterized by a decline in both variables during nighttime compared to daytime [39, 40]. During non-rapid eye movement sleep, this decline in blood pressure is due to reduced cardiac output and is caused by a reduction in heart rate and normal/reduced stroke volume, and a decrease in peripheral resistance [41], owing to a reduction in sympathetic tone [42—441. The diminishing in heart rate is due to a withdrawal of sympathetic activity and an increase in parasympathetic tone [21, 40]. A blunted decline in arterial blood pressure

during night has been observed in IDDM and NIDDM patients with diabetic nephropathy [1, 7, 8]. The pathophysiological factors

the glomerular capillary barrier, and the transglomerular hydraulic pressure difference. Before discussing the different determinants it should be recalled that diurnal changes in albuminuria is present during 24-hour recumbency and during spaced identical meals (protein intake) [2, 28—30]. Diurnal alterations in serum albumin concentration cannot explain the reduction in albuminuria from day to night in non-diabetic nephropathies [2]. Changes

in the size and charge selective properties of the glomerular

responsible for this abnormal day to night variation in arterial blood pressure in diabetic nephropathy is likely to be multifactorial; latent fluid retention [121 and cardiac and neurohumoral autonomic dysfunction may play roles in this mechanism. Our finding of a positive correlation between the night/day ratio of

heart rate and the night/day ratio of arterial blood pressure suggest that there is a relative lack of sympathetic withdrawal during sleep, which might be an important feature of nocturnal

capillary wall is well documented in IDDM patients with diabetic hypertension in diabetic nephropathy. This suggestion is based on nephropathy [31—34]. However, we have no information on diur- recent 24-hour ECG findings showing that diminished day/night nal variations in these properties of the glomerular capillary wall difference in mean RR interval, that is, heart rate, in subjects with

584

Hansen et al: BP and albuminuria in diabetic nephropathy

and without diabetic nephropathy is mainly caused by lack of Acknowledgments withdrawal of sympathetic activity during night [22, 23]. We found We acknowledge the assistance of Ulla M. Smidt and Birgitte V. no significant correlation between the beat-to-beat variation Hansen in conducting the study. during deep breathing (reflects mainly cardiac vagus activity) and Reprint requests to Henrik Post Hansen, Steno Diabetes Center, Niels the degree of arterial blood pressure dipping. Steensens Vej 2, DK-2820 Gentofte, Denmark Diabetic nephropathy is nearly always accompanied by a varying degree of extracellular fluid retention, which seems to play a References dominant role in the initiation and maintenance of arterial blood 1. HANSEN KW, MAU PEDER5EN M, MARSHALL SM, CHRISTIAN5EN JS, pressure elevation in diabetic nephropathy [45]. Recently, Mulec

et at [12] demonstrated that there was no nocturnal decline in arterial blood pressure in IDDM patients with diabetic nephropathy, and an ECV above the median as compared with patients with an ECV below the median. All patients were treated with diuretics, one patient with hydrochlorothiazide, the others with furosemide. Furthermore, nearly 50% received an additional beta-blockade treatment. Their mean GFR was 39 ml min1

MOGENSEN CE: Circadian variation of blood pressure in patients with diabetic nephropathy. Diabetologia 35:1074—1079, 1992

2. KOOPMAN MG, KREDIET RT, KOOMEN GCM, DE MOOR EAM, ARIsz

L: Circadian rhythm of proteinuria: Relationship with molecular weight of proteins and influence of prostaglandin inhibition. Contr Nephrol 68:114—120, 1988 3. KOOPMAN MG, KREDIET RT, ZUYDERHOUDT FMJ, LIE MOOR EAM,

ARIsz L: A circadian rhythm of proteinuria in patients with a nephrotic syndrome. Clin Sci 69:395—401, 1985

1.73 m2. The blunted nocturnal decline in arterial blood pressure in patients with diabetic nephropathy could be due to a re-entry of

4. PICKERING TG, HARSHFIELD GA, KLEINERT HD, BLANK 5, LARAGH

edema fluid into the circulation during recumbency at night,

5. TIDSTRØM B: Quantitative determination of protein in normal urine. Scand J Clin Lab Invest 15:167—172, 1963

causing an increase in intravascular volume [121. This would lead to improved cardiac filling and cardiac output. Our data in IDDM

patients with diabetic nephropathy with well-preserved GFR

[mean (SD) 85 (27) ml min 1.73 m2] do not support the concept that latent overhydration leads to nocturnal hypertension. We found no significant difference in the nocturnal reduction in arterial blood pressure in patients with an ECV below the median, compared to patients with an ECV above the median. The risk of

overlooking a difference in nocturnal arterial blood pressure reduction of more than + 1.7% between patients with an ECV below and patients with an ECV above the median, is less than 5%.

Extracellular fluid volume was calculated according to the method described by BrOchner-Mortensen [26], both in the study of Mulec et al [12] and in the present study. The ECV [mean (SD), 14.2 (1.7) liter- 1.73 m2] in our study is similar to the ECV (14.5 liter 1.73 m2) previously reported in IDDM patients with diabetic nephropathy and well-preserved kidney function (107 ml • min' 1.73 rn—2) [45]. The normal values for ECV presented as percent of body wt is 19.5% in men and 18.8% in women [46]. The difference in ECV between patients above and below the median value of ECV were comparable in the study of Mulec et at [12] and in our study [ECV, mean (5EM), was 12.9 (0.2) liter - 1.73

m2

in group A and 15.4 (0.3) liter - 1.73 m2 in group B], 2.2 liter versus 2.5 liter, respectively. Differences in the degree of impaired kidney function and drug therapy are suggested as the most likely explanations for the discrepancy between the past [12] and the present studies. Enhanced nighttime sodium excretion rate has been demonstrated in hypertensive patients with loss of nocturnal

decline in arterial blood pressure [47] and in some diabetic patients with autonomic neuropathy [11]. Our study showed a tendency for a reverse night/day urinary excretion rate of sodium.

In conclusion, our study indicates an association between arterial blood pressure and albuminuria, but the mechanisms involved in the reduction of albuminuria from day to night are attributed largely to mechanisms other than blood pressure changes. A relative lack of sympathetic withdrawal during sleep

seems to be an important feature of nocturnal hypertension in diabetic nephropathy.

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