Correspondence
Increase in Nocturnal Blood Pressure and Progression to Microalbuminuria in Diabetes
N Engl J Med 2003; 348:260-264January 16, 2003
- Article
To the Editor:
Lurbe et al. (Sept. 12 issue)1 report that the normal decrease in nocturnal blood pressure may be blunted before the development of microalbuminuria in patients with type 1 diabetes. The authors' suggestion that subtly increased blood pressure is the mechanism behind the nephropathy may be an oversimplification. Although average blood pressure was slightly higher in the patients in whom microalbuminuria subsequently developed, hyperglycemia and higher heart rates were also more common in these patients. Altered autonomic tone may be associated with all these observations, including the increased rate of microalbuminuria.
In patients with diabetes, nocturnal heart-rate variability is blunted, reflecting an altered sympathetic–parasympathetic balance2; the higher nocturnal heart rates in the study by Lurbe et al. can be attributed to this physiologic process. Glycemia may be correlated with increased sympathetic tone — in the presence and in the absence of diabetes.3,4 Finally, there is now evidence that sympathetic overactivity, independently of blood pressure, can accelerate nephropathy.5
If autonomic tone is what we are measuring with 24-hour blood-pressure monitoring, then perhaps we should consider other options for measuring it. For example, at our institution, ambulatory blood-pressure monitoring for 24 hours costs $279, whereas measurement of heart-rate variability with respiratory maneuvers can be performed in 20 minutes at a cost of $170. Before we advocate ambulatory blood-pressure monitoring to predict which patients with diabetes will have subsequent target-organ disease, we should determine whether the alterations in autonomic balance that are probably responsible for the findings reported by Lurbe et al. can be identified by other (perhaps less expensive) means.
5 ReferencesDaniel J. Brotman, M.D.
John P. Girod, D.O.
Sabu Thomas, M.D.
Cleveland Clinic Foundation, Cleveland, OH 44195
brotmad@ccf.org 1
Lurbe E ,Redon J ,Kesani A , et al. Increase in nocturnal blood pressure and progression to microalbuminuria in type 1 diabetes. N Engl J Med 2002;347:797-805
Full Text | Web of Science | Medline2
Bernardi L ,Ricordi L ,Lazzari P , et al. Impaired circadian modulation of sympathovagal activity in diabetes: a possible explanation for altered temporal onset of cardiovascular disease. Circulation 1992;86:1443-1452
Web of Science | Medline3
Panzer C ,Lauer MS ,Brieke A ,Blackstone E ,Hoogwerf B . Association of fasting plasma glucose with heart rate recovery in healthy adults: a population-based study. Diabetes 2002;51:803-807
CrossRef | Web of Science | Medline4
Makimattila S ,Schlenzka A ,Mantysaari M , et al. Predictors of abnormal cardiovascular autonomic function measured by frequence domain analysis of heart rate variability and conventional tests in patients with type 1 diabetes. Diabetes Care 2000;23:1686-1693
CrossRef | Web of Science | Medline5
Strojek K ,Grzeszczak W ,Gorska J ,Leschinger MI ,Ritz E . Lowering of microalbuminuria in diabetic patients by a sympathicoplegic agent: novel approach to prevent progression of diabetic nephropathy? J Am Soc Nephrol 2001;12:602-605
Web of Science | Medline
To the Editor:
Lurbe et al. define abnormal blood pressure as a ratio of nighttime to daytime systolic pressure of more than 0.90, which was found in 43 percent of the patients with normoalbuminuria. We have proposed the 90th percentile (ratio of nighttime to daytime systolic pressure, 0.95) as a more appropriate cutoff point.1
Urinary albumin excretion was essentially unchanged during the 28 months from the first evaluation (11.6 mg per 24 hours) to the final evaluation (16.8 mg per 24 hours) in patients in whom microalbuminuria subsequently developed. This very unexpected finding conflicts with the natural history, which is characterized by a gradual increase in urinary albumin excretion in patients with progression to microalbuminuria.
At the first evaluation, the two groups had the same ratio of nighttime to daytime systolic pressure, and the frequency of microalbuminuria was similar in patients with a normal pattern of blood pressure and those with an abnormal pattern. Thus, ambulatory blood-pressure monitoring two years before progression to microalbuminuria cannot predict this event. The finding of high nighttime blood pressure at the final measurement, just before the patients met the criteria for microalbuminuria, is of limited clinical value. At this late stage of progression to microalbuminuria, the demonstration of elevated nighttime blood pressure suggests a parallel progression of the kidney disease and increase in nighttime blood pressure.
There is a large overlap in the ratio of nighttime to daytime blood pressure both between normoalbuminuric patients with progression to microalbuminuria and those without progression2 and between patients with normoalbuminuria and those with microalbuminuria.3 Ambulatory blood pressure cannot predict the development of microalbuminuria years ahead. An early increase in the indicator itself (urinary albumin excretion) within the normoalbuminuric range is still the most useful risk factor.
3 ReferencesPer Løgstrup Poulsen, M.D., D.M.Sc.
Klavs Würgler Hansen, M.D., D.M.Sc.
Carl Erik Mogensen, M.D., D.M.Sc.
Aarhus Kommunehospital, DK-8000 Aarhus C, Denmark
logstrup@dadlnet.dk 1
Hansen KW ,Poulsen PL ,Ebbehoj E ,Mogensen CE . What is hypertension in diabetes? Ambulatory blood pressure in 137 normotensive and normoalbuminuric Type 1 diabetic patients. Diabet Med 2001;18:370-373
CrossRef | Web of Science | Medline2
Poulsen PL ,Hansen KW ,Mogensen CE . Ambulatory blood pressure in the transition from normo- to microalbuminuria: a longitudinal study in IDDM patients. Diabetes 1994;43:1248-1253
CrossRef | Web of Science | Medline3
Hansen KW ,Christensen CK ,Andersen PH ,Pedersen MM ,Christiansen JS ,Mogensen CE . Ambulatory blood pressure in microalbuminuric type I diabetic patients. Kidney Int 1992;41:847-854
CrossRef | Web of Science | Medline
To the Editor:
Lurbe et al. found that progression to microalbuminuria was preceded by increased nocturnal blood pressure in patients with type 1 diabetes. However, it is questionable whether this conclusion can be generalized to all patients with type 1 diabetes, since the poor metabolic control (glycosylated hemoglobin level, approximately 10.0 percent) in their patients may have influenced the results. Moreover, fixed intervals, instead of the patient's records, were used to define daytime and nighttime periods, which may have led to misclassification. Nocturnal blood pressure is associated with the glycosylated hemoglobin level,1 and inclusion of both variables in the same regression model may therefore be inappropriate.2 Finally, microalbuminuria may be transient, and reversal to normoalbuminuria occurs in about 30 percent of patients with type 1 diabetes.3
We previously reported4 that a blunted fall in nocturnal blood pressure in normotensive patients with type 1 diabetes and normoalbuminuria was associated with increased levels of urinary albumin excretion (within the normal range) and with a predominance of sympathetic activity. Furthermore, after a similar follow-up period (mean [±SD], 66.0±38.9 months) in 51 patients with type 1 diabetes (mean age, 34.0±8.2 years; duration of diabetes, 10.5±7.6 years), we found that only 1 patient had progression to microalbuminuria, and another had progression to proteinuria. The better metabolic control (glycosylated hemoglobin level, 8.1±1.8 percent; reference range, 4.6 to 6.0 percent) in our patients may explain the differences between our results and those of Lurbe et al. We hypothesize that glycemic control, rather than nocturnal blood pressure, is the main determinant of progression to microalbuminuria in patients with type 1 diabetes.
4 ReferencesMaria Luiza Caramori, M.D.
Miriam Pecis, M.D.
Mirela J. Azevedo, M.D.
Hospital de Clinicas de Porto Alegre, Porto Alegre 90035-003, Brazil
mirela@hotnet.net 1
Torbjornsdotter TB ,Jaremko GA ,Berg UB . Ambulatory blood pressure and heart rate in relation to kidney structure and metabolic control in adolescents with Type 1 diabetes. Diabetologia 2001;44:865-873
CrossRef | Web of Science | Medline2
Multiple regression and correlation. In: Zar JH. Biostatistical analysis. 4th ed. Upper Saddle River, N.J.: Prentice-Hall, 1999:413-51.
3
Caramori ML ,Fioretto P ,Mauer M . The need for early predictors of diabetic nephropathy risk: is albumin excretion rate sufficient? Diabetes 2000;49:1399-1408
CrossRef | Web of Science | Medline4
Pecis M ,Azevedo MJ ,Moraes RS ,Ferlin EL ,Gross JL . Autonomic dysfunction and urinary albumin excretion rate are associated with an abnormal blood pressure pattern in normotensive normoalbuminuric type 1 diabetic patients. Diabetes Care 2000;23:989-993
CrossRef | Web of Science | Medline
To the Editor:
Lurbe and colleagues report that the nondipping status precedes the development of microalbuminuria in normotensive patients with type 1 diabetes. Moreover, when microalbuminuria and a reduced fall in nocturnal blood pressure are detected in persons with type 1 diabetes, hypertension is usually absent, whereas persons with type 2 diabetes usually have overt hypertension when microalbuminuria and a nondipping status are first detected.1
We investigated the relation between urinary albumin excretion and morning blood-pressure variations in 31 normotensive patients with newly diagnosed type 2 diabetes. In a comparison of patients who did not have microalbuminuria with those who did, the latter had significantly higher morning blood pressure (P<0.003), whereas daytime and nighttime blood pressures were similar in the two groups (Table 1Table 1
Characteristics of Patients with Type 2 Diabetes According to the Presence or Absence of Microalbuminuria.). The association between morning blood pressure and microalbuminuria persisted after adjustment for potential confounders such as sex, age, and duration of diabetes.Blood pressure falls markedly in the nighttime because of the reduction in sympathetic activity that is brought about by sleep and then increases steeply in the morning when the person awakens and resumes his or her daily activities.2 In patients with type 2 diabetes, this increase occurs together with a peak incidence in the onset of acute cardiovascular disease in the morning hours,3 which is why an enhanced rise in morning blood pressure is widely regarded as an adverse phenomenon that needs to be counteracted by the blood-pressure–lowering effect of treatment.4 The increase in morning blood pressure and microalbuminuria coexist in normotensive patients with newly diagnosed type 2 diabetes and may contribute to the increased cardiovascular risk among these patients.
4 ReferencesRaffaele Marfella, M.D.
Katherine Esposito, M.D.
Dario Giugliano, M.D.
Second University Naples, 80138 Naples, Italy
raffaele.marfella@unina2. it 1
Sowers JR ,Epstein M ,Frohlich ED . Diabetes, hypertension, and cardiovascular disease: an update. Hypertension 2001;37:1053-1059[Erratum, Hypertension 2001;37:1350.]
Web of Science | Medline2
Mancia G ,Ferrari A ,Gergorini L , et al. Blood pressure and heart rate variabilities in normotensive and hypertensive human beings. Circ Res 1983;53:96-104
Web of Science | Medline3
Muller JE ,Tofler GH ,Stone PH . Circadian variation and triggers of onset of acute cardiovascular disease. Circulation 1989;79:733-743
CrossRef | Web of Science | Medline4
Mulcahy D . “Circadian“ variation in cardiovascular events and implications for therapy? J Cardiovasc Pharmacol 1999;34:Suppl 2:S3-S8
Web of Science | Medline
Author/Editor Response
We agree with Brotman and colleagues that nocturnal hypertension and an elevated heart rate in patients with diabetes may reflect an altered sympathetic–parasympathetic balance. Blood pressure and its circadian variation depend on multiple factors, not only autonomic tone. The idea that hyperglycemia increases sympathetic tone and, independently of blood pressure, accelerates nephropathy is nevertheless intriguing. Consideration of the cost of testing was beyond the scope of our article.
Poulsen and associates suggest a nighttime-to-daytime ratio of 0.95 as a criterion for nocturnal hypertension. We chose the widely used but equally arbitrary ratio of 0.90 as a cutoff point.1 They note the absence of a significant increase in urinary albumin excretion, within the normoalbuminuric range, in the patients in our study in whom microalbuminuria ultimately developed. The increase in nocturnal blood pressure occurred during a mean interval of 28 months, during which urinary albumin excretion had not changed significantly (from 11.6 to 16.8 mg per 24 hours).2 Thus, our key finding, an increase in nocturnal blood pressure that antedated the development of microalbuminuria, is not affected by our not having documented a gradual increase in urinary albumin excretion. Regardless of whether an increase in urinary albumin excretion within the normoalbuminuric range is or is not a good marker of progression, a normal ratio of nighttime to daytime systolic blood pressure has a strong negative predictive value for the development of microalbuminuria.2
Caramori et al. comment on glycemic control. We stated that a higher level of glycosylated hemoglobin is a predictor of the risk of microalbuminuria.2 The patients in their study were older and possibly more compliant with regard to insulin and diet, which may explain, in part, the low rate of progression to microalbuminuria. In the absence of an elevation in blood pressure, however, poor glycemic control alone may not have a decisive role in the progression to microalbuminuria, as suggested by our subgroup analysis based on the glycosylated hemoglobin level.2 Moreover, progression to overt nephropathy is influenced by the blood pressure level perhaps more than by the degree of glycemic control.3 Regarding fixed intervals as compared with the patient's records, the nighttime-to-daytime ratio taken from a fixed interval avoids transitional effects and, in our experience, yields results similar to those with self-reporting.
Marfella et al. provide their data from patients with type 2 diabetes. We appreciate the importance of examining blood pressure in the early morning hours because of the high incidence of cardiovascular events at this time of the day.4 Their data, however, show normal blood pressure in the clinic, which is contrary to the view that patients with type 2 diabetes are clearly hypertensive when microalbuminuria develops.5
5 ReferencesEmpar Lurbe, M.D.
Josep Redon, M.D.
Hospital General de Valencia, 46014 Valencia, SpainDaniel Batlle, M.D.
Feinberg School of Medicine at Northwestern University, Chicago, IL 60611
d-batlle@nwu.edu 1
Verdecchia P ,Schillaci G ,Guerrieri M , et al. Circadian blood pressure changes and left ventricular hypertrophy in essential hypertension. Circulation 1990;81:528-536
CrossRef | Web of Science | Medline2
Lurbe E ,Redon J ,Kesani A , et al. Increase in nocturnal blood pressure and progression to microalbuminuria in type 1 diabetes. N Engl J Med 2002;347:797-805
Full Text | Web of Science | Medline3
Microalbuminuria Collaborative Study Group
CrossRef | Web of Science4
Redon J ,Bertolin V ,Giner V ,Lurbe E . Assessment of blood pressure early morning rise. Blood Press Monit 2001;6:207-210
CrossRef | Web of Science | Medline5
Parving HH ,Lehnert H ,Brochner-Mortensen J ,Gomis R ,Andersen S ,Arner P . The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870-878
Full Text | Web of Science | Medline
- Citing Articles (2)
Citing Articles
1
Naoto Ashizawa, Shinji Seto, Yoshisada Shibata, Katsusuke Yano. (2007) Bedtime Administration of Cilnidipine Controls Morning Hypertension. International Heart Journal 48:5, 597-603
CrossRef2
C. E. Mogensen, M. E. Cooper. (2004) Diabetic renal disease: from recent studies to improved clinical practice. Diabetic Medicine 21:1, 4-17
CrossRef
