Background Patients with type 1 diabetes mellitus and microalbuminuriaoften have elevated blood pressure while they are asleep, butit is not known whether the elevation develops concomitantlywith microalbuminuria or precedes it.
Methods We monitored 75 adolescents and young adults who hadhad type 1 diabetes with normal urinary albumin excretion andblood pressure for more than five years. Ambulatory blood-pressuremonitoring was used to assess blood pressure at the initialevaluation and about two years later, at which time all subjectshad normal urinary albumin excretion. Subsequently, subjectswere monitored for the development of microalbuminuria.
Results Microalbuminuria developed in 14 subjects, whereas theother 61 continued to have normal urinary albumin excretion.The mean (±SD) systolic pressure during sleep increasedsignificantly in the subjects who ultimately had microalbuminuria(from 109.9±11.3 to 114.9±11.7 mm Hg, P=0.01)but not in the subjects with normal albumin excretion (from106.0±8.8 to 106.4±14.8 mm Hg). The risk of progressionto microalbuminuria was examined in relation to the ratio ofsystolic pressure during sleep to systolic pressure in the daytime.A ratio of 0.9 or lower, used to define a normal fall in nocturnalpressure, had a negative predictive value of 91 percent forthe development of microalbuminuria. Moreover, the risk of microalbuminuriawas 70 percent lower (95 percent confidence interval, 44 to110 percent) in subjects with a ratio of 0.9 or less than inthose with a ratio higher than 0.9 (P=0.01).
Conclusions In persons with type 1 diabetes, an increase insystolic blood pressure during sleep precedes the developmentof microalbuminuria. In those whose blood pressure during sleepdecreases normally, the progression from normal albumin excretionto microalbuminuria appears to be less likely.
Among persons with type 1 diabetes mellitus who have normalurinary albumin excretion, the prevalence of hypertension, determinedon the basis of blood-pressure readings at office visits, issimilar to that in the general population.1,2 Moreover, whenmicroalbuminuria is detected in persons with type 1 diabetes,indicating the presence of incipient nephropathy, hypertensionis usually absent, whereas persons with type 2 diabetes usuallyhave overt hypertension when microalbuminuria is first detected.2,3,4Thus, if one uses the conventional definition of hypertension,or even the more stringent definition recently proposed forpersons with diabetes (i.e., systolic blood pressure that exceeds129 mm Hg and diastolic blood pressure that exceeds 79 mm Hg),5one must conclude that in persons with type 1 diabetes who aresusceptible to kidney disease, hypertension does not developuntil microalbuminuria is established.
However, more recent studies with the use of ambulatory blood-pressuremonitoring have shown that subjects with type 1 diabetes andmicroalbuminuria have higher nocturnal blood pressure than eithersubjects with type 1 diabetes and normal urinary albumin excretionor age-matched controls.6,7,8,9,10,11,12,13 Such studies haveshown that persons with type 1 diabetes and incipient nephropathyoften have associated nocturnal hypertension.
On the basis of a previous cross-sectional study, we suggestedthat in persons with type 1 diabetes and incipient nephropathy,nocturnal hypertension may antedate the development of microalbuminuria.6Alternatively, the two conditions may develop concomitantly,as others have suggested.13 It is important to determine whethernocturnal hypertension develops before microalbuminuria or atthe same time, in view of increasing evidence that the riskof progression to overt nephropathy is strongly influenced bythe level of blood pressure, perhaps more than by the degreeof glycemic control.14 If an elevation in blood pressure, manifestedas nocturnal hypertension, antedates the development of microalbuminuria,this finding might be useful as a potential marker of nephropathyand might provide a rationale for treating susceptible personsbefore the onset of microalbuminuria. To address this issue,we performed ambulatory blood-pressure monitoring in a prospectivestudy of adolescents and young adults with type 1 diabetes whohad normal urinary albumin excretion at the time of enrollmentin the study.
Methods
Subjects and Study Design
We recruited 75 subjects from the pediatrics and diabetes outpatientclinics of Hospital General in Valencia, Spain, and Hospitalde Sagunto in Sagunto, Spain, to participate in the study. Allthe subjects had type 1 diabetes according to the standard criteriaof an onset in childhood and insulin dependency. In all subjects,the diagnosis of diabetes had been made at least five yearsbefore enrollment. At the time of enrollment, none of the subjectshad clinical evidence of diabetic complications, such as proliferativeretinopathy, clinical neuropathy, or nephropathy. To be enrolledin the study, subjects had to have normal urinary albumin excretionand normal blood pressure. Normal blood pressure, measured atan office visit, was defined as pressure that was lower than130/80 mm Hg in adults and less than the 95th percentile forage and sex in adolescents (as reported by the Task Force onBlood Pressure Control in Children).15 No subjects had everreceived antihypertensive therapy. Ambulatory blood-pressuremonitoring was performed at intervals of approximately two yearsas long as urinary albumin excretion remained normal. Subjectswere followed prospectively, with measurement of urinary albuminexcretion every three months. Those in whom microalbuminuriadeveloped were withdrawn from the study, since they were generallygiven an angiotensin-converting–enzyme inhibitor as partof standard treatment at that point. Urinary albumin excretionwas measured in two separate 24-hour urine specimens with theuse of a nephelometric immunoassay (Behring Institute; normalrange, 0 to 29 mg per 24 hours). Microalbuminuria was definedas a value for urinary albumin excretion that ranged from 30to 299 mg per 24 hours, as confirmed by two consecutive measurementsless than six months apart.
The study was approved by the committees for the protectionof human subjects of Hospital General and Hospital de Sagunto.All participants gave written informed consent. If a subjectwas younger than 18 years of age, a parent signed the consentform as well.
Blood-Pressure Measurements
At each office visit, blood pressure was measured three timeswhile the subject was seated, after a five-minute rest, withthe use of a mercury sphygmomanometer. The first Korotkoff phasewas used to signify systolic pressure and the fifth phase toindicate diastolic pressure. The mean of the three readingswas recorded as the blood pressure for each office visit. Ambulatoryblood-pressure monitoring was performed with a portable oscillometricrecorder (Spacelabs 90207). Recording began between 8:30 and9 a.m. The pressure was measured at 20-minute intervals from6 a.m. until midnight and at 30-minute intervals from midnightuntil 6 a.m. The most appropriate cuff was selected from thefour sizes supplied by the manufacturer (10 by 13 cm, 13 by24 cm, 24 by 32 cm, and 32 by 42 cm).
For the purpose of ambulatory blood-pressure monitoring, twodifferent periods were defined. The daytime period includedall readings obtained from 8 a.m. until 10 p.m., and the nighttimeperiod included all readings from midnight until 6 a.m. Datafrom 10 p.m. until midnight and from 6 a.m. until 8 a.m. werenot included in the data for the daytime and nighttime periods,respectively, in order to minimize overlaps but were includedin the analysis of the 24-hour data. The mean values for allthe readings of systolic and diastolic pressure during a daytimeor nighttime period were recorded as the systolic and diastolicpressure for that period.6,16,17 A value of 0.9 or lower forthe ratio of the mean nighttime systolic pressure to the meandaytime systolic pressure was defined as the normal drop inblood pressure during sleep. In a pilot study of 24 young adultswith type 1 diabetes and normal urinary albumin excretion, thereproducibility of this ratio was assessed with the use of theBland and Altman method, which is an approach based on a graphictechnique with calculations.17 The mean (±SD) intervalbetween the two measurements in the pilot study was 10.6±4.6months. All subjects had normal pressure (daytime, 120.2/74.9mm Hg; nighttime, 104.6/59.2 mm Hg). The coefficients of repeatabilitywere as follows: daytime systolic pressure, 0.19; daytime diastolicpressure, 0.28; nighttime systolic pressure, 0.17; nighttimediastolic pressure, 0.26; ratio of nighttime to daytime systolicpressure, 0.37; ratio of nighttime to daytime diastolic pressure,0.33. These relatively low coefficients reflect good reproducibility.17
Statistical Analysis
We used the Wilcoxon rank-sum test to compare the subjects inwhom microalbuminuria developed with those in whom it did not.The associations between several variables and the relativerisk of microalbuminuria were calculated with the use of logistic-regressionanalysis. Positive and negative predictive values were calculatedas previously described.18 We used Kaplan–Meier survivalanalysis to determine the probability that microalbuminuriawould develop in the subjects with a normal fall in nocturnalblood pressure and those without a normal fall in nocturnalpressure, comparing the two groups with the use of the log-ranktest. A P value of less than 0.05 (based on the Mann–Whitneytest) was considered to indicate statistical significance. Thedifference in the risk of microalbuminuria between the groupswas calculated on the basis of the crude rate of microalbuminuriawith the use of SPSS software.18
Results
Characteristics of the Subjects at Enrollment
At the time of enrollment, urinary albumin excretion was normalin all subjects (mean level, 11.7±13.2 mg per 24 hours).Blood pressure measured at the initial office visit was alsonormal in all subjects (systolic pressure, 119.9±10.2mm Hg; diastolic pressure, 75.8±8.8 mm Hg). The meanvalues for 24-hour ambulatory blood pressure were in the normalrange (daytime systolic and diastolic pressure, 119.8±9.1and 73.4±6.8 mm Hg, respectively; nighttime systolicand diastolic pressure, 106.7±9.2 and 60.1±6.1mm Hg, respectively).6,16
Urinary Albumin Excretion and Progression to Microalbuminuria
After a mean follow-up of 63.0±9.3 months (range, 23to 108), microalbuminuria developed in 14 of the 75 subjects(19 percent); urinary albumin excretion in this group increasedfrom 11.6±8.5 to 108.7±85.0 mg per 24 hours (P<0.001)(Figure 1A) — a conversion rate similar to that reportedin other studies.19,20 Urinary albumin excretion remained normalin these 14 subjects for a mean of 27.8±16.0 months (range,9 to 68) after the initial evaluation. In the other 61 subjects(81 percent), microalbuminuria did not develop during a meanfollow-up period of 66±21 months (range, 21 to 120) (Figure 1B).In these subjects, urinary albumin excretion remained withinthe normal range (from 11.8±7.9 to 14.0±7.8 mgper 24 hours) after more than five years of follow-up (Figure 1B).
Figure 1. Urinary Albumin Excretion over Time in 75 Subjects with Type 1 Diabetes.
Panel A shows mean urinary albumin values in the 14 subjects in whom microalbuminuria (defined as excretion of 30 to 299 mg per 24 hours) ultimately developed, and Panel B shows values in the 61 subjects in whom urinary albumin excretion remained within the normal range (defined as excretion of less than 30 mg per 24 hours). The bar below each panel indicates the period of normal urinary albumin excretion. I bars indicate standard deviations.
The 14 subjects in whom microalbuminuria ultimately developedare henceforth referred to as the microalbuminuria group, andthe 61 subjects in whom urinary albumin excretion remained normalare referred to as the normoalbuminuria group.
Characteristics of the Two Groups
The group of subjects in whom microalbuminuria ultimately developedand the group with normoalbuminuria were similar with respectto age, sex distribution, body-mass index, and base-line urinaryalbumin excretion (Table 1). The duration of disease, definedby the time elapsed since the diagnosis of diabetes, was shorterin the microalbuminuria group than in the normoalbuminuria group(P<0.001), and the glycosylated hemoglobin level was higherin the microalbuminuria group (P=0.01). The two groups did notdiffer significantly with regard to either systolic or diastolicpressure, measured in the office (Table 1). Likewise, totalcholesterol and triglyceride levels did not differ significantlybetween the two groups (data not shown). In the course of thestudy, proliferative retinopathy developed in 5 subjects (1of 14 in the microalbuminuria group and 4 of 61 in the normoalbuminuriagroup), but none of the 5 subjects had clinical evidence ofneuropathy.
Table 1. Characteristics of 75 Subjects with Type 1 Diabetes, According to Whether Microalbuminuria Ultimately Developed.
Ambulatory Blood-Pressure Monitoring
At the initial evaluation, the mean systolic pressure duringthe daytime and nighttime periods did not differ significantlybetween the microalbuminuria group and the normoalbuminuriagroup (Table 1). The daytime diastolic pressure was slightlybut significantly higher in the microalbuminuria group thanin the normoalbuminuria group. The heart rate did not differsignificantly between the two groups during either the daytimeor the nighttime period.
At the final evaluation, the systolic and diastolic pressure,measured in the office, also did not differ significantly betweenthe two groups of subjects (Table 1). In contrast, the diastolicpressure during both the daytime period and the nighttime periodand the systolic pressure at night were significantly higherin the microalbuminuria group than in the normoalbuminuria group.The heart rate was significantly higher in the microalbuminuriagroup at night and during the day (Table 1).
In the microalbuminuria group, the nighttime systolic pressureincreased from 109.9±11.3 mm Hg at the initial evaluationto 114.9±11.7 mm Hg at the last evaluation (P=0.008),whereas in the normoalbuminuria group it remained essentiallyunchanged (106.0±8.8 mm Hg at the initial evaluationand 106.4±14.8 mm Hg at the final evaluation) (Figure 2A).In the microalbuminuria group, diastolic pressure duringsleep also increased (from 62.9±7.3 mm Hg initially to66.4±7.8 mm Hg at the final evaluation), but the increasewas not statistically significant (P=0.06). Diastolic pressureduring sleep did not change significantly in the normoalbuminuriagroup (from 59.5±5.7 mm Hg initially to 60.1±6.5mm Hg). There was little change in the systolic and diastolicpressure during the daytime period in either group (Table 1).
Panel A shows nocturnal systolic pressure in the 14 subjects in whom microalbuminuria ultimately developed and in the 61 subjects in whom urinary albumin excretion remained normal. Panel B shows nocturnal systolic pressure in the normoalbuminuria group according to the mean (±SD) level of glycosylated hemoglobin (HbA1c). The final evaluation was the last evaluation during follow-up in the normoalbuminuria group and the last evaluation before the development of microalbuminuria in the microalbuminuria group. I bars indicate standard deviations.
Logistic-regression analysis showed that an increase in nighttimesystolic pressure was significantly related to the developmentof microalbuminuria. For each 5 mm Hg increase in nighttimesystolic pressure, the relative risk of microalbuminuria was1.44 (95 percent confidence interval, 1.03 to 2.02). In thesame model, for each 1 percent increase in the glycosylatedhemoglobin level, the relative risk of microalbuminuria was1.66 (95 percent confidence interval, 1.13 to 2.44).
Progression to Microalbuminuria According to the Ratio of Nighttime to Daytime Pressure
An abnormal pattern of nighttime blood pressure is often describedin terms of the ratio of nighttime to daytime pressure.6,21,22We defined an abnormal pattern as a ratio higher than 0.9.21,22At the initial evaluation, 43 of the 75 subjects in our studyhad a normal pattern of nighttime blood pressure and 32 hadan abnormal pattern (Figure 3). The distribution was similarat the final evaluation, although a change in the pattern wasobserved in six subjects (from a normal to an abnormal patternin three subjects and from an abnormal to a normal pattern inthe other three). At the initial evaluation, there were no significantdifferences in daytime systolic or diastolic pressure betweensubjects with a normal pattern of nighttime pressure and thosewith an abnormal pattern (daytime systolic pressure, 120.9±10.0and 118.5±7.38 mm Hg, respectively; P=0.21; daytime diastolicpressure, 74.8±7.08 and 71.8±6.37 mm Hg, respectively;P=0.08). As expected, nighttime blood pressure was higher inthe subjects with an abnormal pattern than in those with a normalpattern (nighttime systolic pressure, 112±8.33 mm Hgvs. 102.9±8.04 mm Hg; nighttime diastolic pressure, 63.1±5.28mm Hg vs. 58.1±5.82 mm Hg; P<0.001 for both comparisons),reflecting the criteria used to define normal and abnormal patternsof nighttime pressure. There were no significant differencesbetween the subjects who had a normal pattern of nocturnal pressureand those who had an abnormal pattern with regard to age (23.3±12.6and 18.7±8.4 years, respectively; P=0.07), the durationof disease (14.3±7.27 and 13.4±5.07 years, P=0.49),urinary albumin excretion (13.1±14.5 and 13.8±10.8mg per 24 hours, P=0.52), or the glycosylated hemoglobin level(9.1±1.60 and 9.9±1.80 percent, P=0.14).
Figure 3. Ratio of Nighttime to Daytime Systolic Blood Pressure at the Initial Evaluation.
A ratio of 0.9 or lower was defined as a normal nocturnal pattern, and a ratio higher than 0.9 as an abnormal nocturnal pattern.
Microalbuminuria developed in only 7 of the 43 subjects witha normal pattern of nocturnal blood pressure at the initialevaluation and in only 4 of the 43 with a normal pattern atthe final evaluation. As a marker of progression to microalbuminuria,a normal pattern of nocturnal blood pressure had a negativepredictive value of 84 percent and 91 percent, respectively,at the initial and final evaluations, indicating a low risk.Microalbuminuria developed in 7 of the 32 subjects classifiedas having an abnormal pattern of nocturnal pressure at the initialevaluation and in 10 of the 32 classified as having an abnormalpattern at the last evaluation during the period of normal urinaryalbumin excretion. The positive predictive value of an abnormalpattern of nocturnal pressure for the progression to microalbuminuriawas 22 percent at the initial evaluation and 31 percent at thelast evaluation during the period of normoalbuminuria.
Kaplan–Meier analysis showed that the risk of progressionto microalbuminuria differed significantly between the subjectswith a normal pattern of nocturnal blood pressure and thosewith an abnormal pattern (Figure 4). On the basis of the finalevaluation, the risk of microalbuminuria in the group of subjectswith a normal pattern of nocturnal blood pressure was 70 percentlower than the risk in the group with an abnormal pattern (95percent confidence interval, 44 to 110 percent).
Figure 4. Kaplan–Meier Curves Showing the Probability of Microalbuminuria According to the Pattern of Daytime and Nighttime Systolic Pressure.
The probability of microalbuminuria differed significantly between the two groups (P=0.01 by the log-rank test; chi-square=6.217 with 1 df). The risk of microalbuminuria was 70 percent lower in the subjects with a normal nocturnal pattern than in those with an abnormal nocturnal pattern.
Subgroup Analysis According to the Glycosylated Hemoglobin Level
At the initial evaluation and during follow-up, glycosylatedhemoglobin levels were higher in the subjects in whom microalbuminuriaultimately developed than in those in whom it did not (Table 1).As noted above, logistic-regression analysis indicated thatthe value for glycosylated hemoglobin was significantly relatedto the risk of microalbuminuria. Thus, our data confirm theobservation that poor glycemic control is a predictor of microalbuminuria.19,23
To address the question of whether poor metabolic control orhigh nocturnal systolic pressure accounted for the progressionto microalbuminuria, we performed a separate analysis of datafrom ambulatory blood-pressure monitoring in 16 of the 61 subjectsin the normoalbuminuria group; these 16 subjects had levelsof glycosylated hemoglobin that were as high as those in themicroalbuminuria group (Table 2). In this subgroup of 16 subjects,who were similar in age to the 14 subjects in the microalbuminuriagroup, urinary albumin excretion at the initial evaluation wasin the normal range and was similar to that in the microalbuminuriagroup (Table 2). The mean values for systolic and diastolicpressure, measured at the initial office visit, were 119.5±9.9and 75.5±9.2 mm Hg, respectively; the values were nearlythe same at the end of the normoalbuminuric period (Table 2).Analysis of data from ambulatory blood-pressure monitoring showedthat daytime blood pressure did not differ significantly betweenthis subgroup and the microalbuminuria group. In contrast, systolicpressure during sleep was significantly lower in the subgroupwith normoalbuminuria and high glycosylated hemoglobin levelsthan in the microalbuminuria group (104.9±6.6 vs. 114.9±11.7mm Hg, P=0.003).
Table 2. Characteristics of the Subjects in Whom Microalbuminuria Ultimately Developed and the Subgroup of Subjects with Normoalbuminuria and an Elevated Level of Glycosylated Hemoglobin at the Final Evaluation.
Systolic pressure during sleep did not change significantlyduring the course of the study in the 45 subjects in the normoalbuminuriagroup who had lower levels of glycosylated hemoglobin (7.9±0.9percent) (Figure 2B). Diastolic pressure at night, as well asboth systolic and diastolic blood pressure during the day, didnot change significantly in either subgroup of subjects in whomurinary albumin excretion remained normal (data not shown).
Discussion
In this study, which involved a cohort of adolescents and youngadults with type 1 diabetes, an increase in blood pressure duringsleep, detected by ambulatory blood-pressure monitoring, precededthe development of microalbuminuria. In contrast, in subjectsin whom microalbuminuria did not develop during a follow-upperiod of more than five years, neither nighttime nor daytimeblood pressure increased significantly.
Thus, the risk of microalbuminuria, a marker of kidney diseasein patients with type 1 diabetes,19,23,24 appears to be verylow in patients who remain normotensive, as defined not onlyby normal blood-pressure readings at office visits and duringambulatory daytime monitoring over time but also by the absenceof an increase in systolic pressure during sleep. We emphasizethese criteria to highlight the fact that neither blood pressureas assessed at office visits nor daytime blood pressure as assessedby ambulatory blood-pressure monitoring changed significantlyover time (i.e., during the period of normoalbuminuria) in subjectsin whom microalbuminuria eventually developed. Thus, an increasein nighttime systolic pressure appears to be the earliest detectablemanifestation of altered blood-pressure regulation in patientswith type 1 diabetes. Our study documented a temporal relationbetween an increase in blood pressure and the development ofincipient diabetic nephropathy as reflected by microalbuminuriain patients with type 1 diabetes.24
An early increase in nighttime arterial blood pressure may havea key role in the development of diabetic nephropathy. For instance,systemic pressure overload, initially restricted to systolicpressure during sleep, when transmitted to the glomerular circulation,may cause intrarenal hemodynamic changes, leading to microalbuminuria,structural renal damage, or both.
Our findings are in keeping with the concept that a predispositionto essential hypertension increases the risk of diabetic nephropathy.This concept is based on studies showing that the parents ofpatients with type 1 diabetes and proteinuria have a higherprevalence of hypertension than that in the general population.25,26,27A different line of evidence that also suggests a common linkbetween a susceptibility to hypertension and diabetic nephropathyamong patients with type 1 diabetes comes from studies showingincreased activity of cellular markers such as the sodium–lithiumexchanger28 and the sodium–hydrogen exchanger in bothsubjects with essential hypertension29 and those with type 1diabetes and nephropathy.30
In accordance with the results of previous studies, our datasuggest that the risk of progression to microalbuminuria isinfluenced by the level of glycosylated hemoglobin.20 Yet microalbuminuriadid not develop in a subgroup of subjects with very poor metaboliccontrol in whom blood pressure remained normal. Although poormetabolic control hastens the progression of renal disease,20nephropathy appears to develop only in susceptible persons withtype 1 diabetes.31,32,33 Since subtle but early elevations inblood pressure antedate the development of microalbuminuria,we surmise that, regardless of the level of metabolic control,an elevation in nocturnal blood pressure plays a key part inthe development of microalbuminuria in susceptible persons withtype 1 diabetes.
Circadian changes in blood pressure can readily be assessedon the basis of the ratio of nighttime to daytime blood pressure.34In our study, a ratio of 0.9 or lower, reflecting the normaldrop in nighttime pressure, had a negative predictive valueof 91 percent for progression to microalbuminuria. The potentialclinical significance of the nighttime drop in blood pressureis further revealed in the associated 70 percent reduction inthe risk of microalbuminuria. Thus, a normal decrease in nocturnalblood pressure is a strong marker of nonprogressive disease.
An evaluation of the risk of nephropathy at an early stage oftype 1 diabetes would provide the best basis for choosing therapiesdesigned to prevent the progression to microalbuminuria. Theabsence of a drop in nocturnal blood pressure has been associatedwith cardiovascular complications in subjects with essentialhypertension35,36 and, more recently, in those with type 1 diabetesand overt nephropathy.37 Early documentation of an increasein nocturnal pressure might warrant the use of agents such asangiotensin-converting–enzyme inhibitors or angiotensinII–receptor blockers in a patient with type 1 diabetes.Documentation of normal nocturnal blood pressure, on the otherhand, might suggest that there is no need for early therapeuticinterventions other than those designed to provide optimal glycemiccontrol.
Supported by grants from the National Institute of Diabetesand Digestive and Kidney Diseases and the Department of VeteransAffairs (to Dr. Batlle).
Presented in part at the annual meeting of the High Blood PressureCouncil of the American Heart Association, Orlando, Fla., September13–16, 1999.
Source Information
From the Pediatric Nephrology Unit, Department of Pediatrics, Hospital General and University of Valencia, Valencia, Spain (E.L., J.T., V.A.); the Hypertension Clinic, Department of Medicine, Hospital Clinico and University of Valencia, Valencia, Spain (J.R.); the Division of Nephrology and Hypertension, Feinberg School of Medicine, Northwestern University, Chicago (A.K., D.B.); and the Department of Medicine, Hospital de Sagunto, Sagunto, Spain (J.M.P.).
Address reprint requests to Dr. Batlle at the Division of Nephrology and Hypertension, Feinberg School of Medicine, Northwestern University, 320 E. Superior St., 10-475 Searle Bldg., Chicago, IL 60611.
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