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Relationship between GFR and Albuminuria in Stage 1 Hypertension Paolo Palatini,* Lucio Mos,† Pierferruccio Ballerini,‡ Adriano Mazzer,‡ Francesca Saladini,* Alessandra Bortolazzi,§ Susanna Cozzio,| and Edoardo Casiglia,* on behalf of the HARVEST Investigators

Summary Background and objectives Whether glomerular hyperfiltration is implicated in the development of microalbuminuria in hypertension is not well known. This prospective study investigated the relationship between changes in GFR and microalbuminuria in hypertension. Design, setting, participants, & measurements This study assessed 534 stage 1 hypertensive participants from the Hypertension and Ambulatory Recording Venetia Study (n=386 men) without microalbuminuria at baseline, who were recruited from 1990 to 1995 and followed for a median of 8.5 years. Mean age was 33.968.6 years and mean BP was 146.6610.5/94.065.0 mmHg. Creatinine clearance and 24-hour urinary albumin were measured at study entry and end. Participants were defined as normofilterers (normo) or hyperfilterers (hyper) according to whether GFR was ,150 or $150 ml/min per 1.73 m2, respectively. Participants were divided into four groups based on GFR changes from baseline to follow-up end: normo→normo (n=395), normo→hyper (n=31), hyper→hyper (n=61), and hyper→normo (n=47). Results Microalbuminuria progressively increased across the four groups and was 5.3% in normo→normo, 9.7% in normo→hyper, 16.4% in hyper→hyper, and 36.2% in hyper→normo (P,0.001). This association held true in a multivariable logistic regression in which several confounders, ambulatory BP, and other risk factors were taken into account (P,0.001). In particular, hyperfilterers whose GFR decreased to normal at study end had an adjusted odds ratio of 7.8 (95% confidence interval, 3.3–18.2) for development of microalbuminuria compared with participants with normal GFR throughout the study.

*Department of Medicine, University of Padova, Padua, Italy; †Town Hospital, San Daniele del Friuli, Italy; ‡Town Hospital, Vittorio Veneto, Italy; § Town Hospital, Rovigo, Italy; and | Town Hospital, Trento, Italy Correspondence: Dr. Paolo Palatini, Department of Medicine, University of Padova, Via Giustiniani, 2 35128 Padova, Italy. Email: [email protected]

Conclusions These data support the hypothesis for a parabolic association between GFR and urinary albumin in the early stage of hypertension. Clin J Am Soc Nephrol 8: 59–66, 2013. doi: 10.2215/CJN.03470412

Introduction Glomerular hyperfiltration has been shown to occur both in animal models and in humans (1–3). Hyperfiltration is hypothesized to be a precursor of intraglomerular hypertension leading to albuminuria (1,2). In the absence of therapeutic interventions, GFR then would fall progressively in parallel with a further rise in albuminuria. This mechanism may lead, in the long run, to end stage renal failure. Glomerular hyperfiltration has been shown to occur in the large majority of young type 1 diabetic patients (4). Some studies have shown that glomerular hyperfiltration may also occur in other clinical conditions, including hypertension (3,5). However, the natural history of changes in GFR and albumin excretion rate (AER) has never been described in participants with high BP. If evidence is given that glomerular hyperfiltration is implicated in determining renal impairment in hypertension, this could help identify a subgroup of patients who may benefit from early antihypertensive treatment. In the Hypertension and www.cjasn.org Vol 8 January, 2013

Ambulatory Recording Venetia Study (HARVEST), we initially measured creatinine clearance and AER in a well characterized cohort of young to middleaged participants screened for stage 1 hypertension (3,6). The same measures were repeated several years later to determine if glomerular hyperfiltration is associated with an accelerated deterioration of renal function compared with nonhyperfiltering participants. The goals of the present analysis were to describe the natural history of GFR in the early stage of hypertension and to elucidate the relationship between changes in GFR and AER over time. Our hypotheses were that normofiltration may represent a state of preserved kidney function and stable AER that does not change significantly in the majority of participants but may reflect a condition of former glomerular hyperfiltration in a subset of individuals who have had a decline in kidney function over time, and that GFR would decrease, in association with an increase in AER among the participants with initial glomerular hyperfiltration. Copyright © 2013 by the American Society of Nephrology

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Clinical Journal of the American Society of Nephrology

Materials and Methods Study Participants The participants took part in the HARVEST, a multicenter study investigating the origin of hypertension with regard to physiologic (6), genetic (7), and clinical (8) characteristics. The study was initiated in April 1990 and is conducted in 17 hypertension units in Italy. Never-treated participants aged 18–45 years screened for stage 1 hypertension were enrolled. Consecutive patients with stage 1 hypertension diagnosed on the basis of office BP measurement seen in the offices of general practitioners and eligible for recruitment were sent to the referral centers (6–8). Recruitment of participants lasted from 1990 to 1995. The specific investigation on glomerular hyperfiltration was carried out in the 534 participants who successfully completed 24-hour urine collection and 24-hour BP recording both at the baseline and at the end of the study. Patients’ mean age was 33.968.6 years and office BP was 146.6610.5/94.065.0 mmHg. Blood and urine samples were taken to the coordinating office in Padova, where they were processed. The higher prevalence of men among our study participants (72.3%) confirms previous observations of a much higher prevalence of men in the young segment of the hypertensive population (9). The study was approved by the Ethics Committee of the University of Padova, and written informed consent was given by the participants. The procedures followed were in accordance with institutional guidelines. Clinical Examination At baseline, all participants underwent physical examination, anthropometry, blood chemistry, urine analysis, office BP and 24-hour BP measurements, electrocardiography, and 24-hour urine collection for AER measurement. Participants completed questionnaires about their lifestyle, including coffee consumption, physical activity, alcohol use, and cigarette smoking. Body mass index (BMI) was considered as an index of adiposity (weight divided by height squared). Creatinine clearance was computed from creatinine excretion in a 24-hour urine collection and a single measurement of serum creatinine, and the data were normalized by body surface area (3). In 360 participants, 24-hour urinary epinephrine and NE assessment was performed by a HPLC method (10). Urine specimens were frozen (220 C°) and sent to the coordinating office at the University of Padova, where they were processed (10). Other details on the methods used in the HARVEST study were reported elsewhere (3,6–8,10). BP Measurement The mean of six readings taken in the supine position during two separate visits was defined as baseline office BP. Twenty-four–hour BP monitoring was performed according to the previously published procedures (6–8) with a Takeda A&D TM2420 model 7 (A&D Co., Tokyo, Japan) or a ICR Spacelabs 90207 monitor (Spacelabs Inc., Redmond, WA). Both devices were previously validated (10). AER Measurement During the 24-hour recordings, urine was collected for AER measurement. Immediately after completion, volumes

were measured and urine specimens were frozen (220 C°) and sent to the coordinating office in Padova (6). Here, the urinary albumin level was measured by a commercially available RIA kit (H ALB kit-double antibody; Sclavo SpA, Cinisello Balsamo, Italy). Results were expressed as milligrams per 24 hours. Participants were categorized as having normoalbuminuria (AER=0–29 mg/24 h) or microalbuminuria (AER $30 mg/24 h). Follow-Up Visits After baseline examination, follow-up visits were scheduled at 1, 2, 3, and 6 months and thereafter at 6-month intervals. During the initial period of observation, participants were given general information about nonpharmacologic measures by the HARVEST investigators. If after at least 6 months of implementation of nonpharmacologic measures, the participant’s BP was above the operational threshold level, the patient was rescheduled for a visit within 2–4 weeks and the average BP was calculated. If BP was still above the limit, the patient reached the end point and was given antihypertensive drug treatment; otherwise, he or she was checked at monthly intervals. The BP operational threshold level was established on the basis of the recommendations of the 1999 World Health Organization/ International Society of Hypertension guidelines (11) and the 2003 and 2007 European Society of Cardiology/European Society of Hypertension guidelines (12,13). Patients who developed sustained hypertension needing antihypertensive medication received the final 24-hour BP, creatinine clearance, and AER assessment before starting therapy. In the patients who remained untreated, the last available BP monitoring, AER measurement, and creatinine clearance were used to calculate final ambulatory BP, microalbuminuria, and GFR, respectively. Median follow-up for the 534 participants was 8.5 years (interquartile range [IQR], 5.4– 11.5 years). Other details on follow-up procedures were reported elsewhere (3,6–8). Patient Classification According to GFR Dynamics Creatinine clearance at entry was .60 ml/min per 1.73 m2 in all of the participants. Participants were defined as normofilterers (normo) or hyperfilterers (hyper) according to whether their GFR was ,150 or $150 ml/min per 1.73 m2, respectively (3,14). Participants were then divided into four groups on the basis of GFR changes from baseline to follow-up end: group 1, normofilterers throughout the study (normo→normo); group 2, normofilterers at baseline and hyperfilterers at study end (normo→hyper); group 3, hyperfilterers throughout the study (hyper→hyper); and group 4, hyperfilterers at baseline and normofilterers at study end (hyper→normo). Statistical Analyses Data are presented as mean 6 SD unless otherwise specified. The distribution of baseline clinical variables was compared across groups using the general linear model procedure and adjusting for age and sex. Non-normally distributed variables were compared with the Kruskal– Wallis test. Changes over time were also adjusted for baseline values. The Tukey–Kramer multiple comparisons post hoc test was used for contrasts. The significance of

Clin J Am Soc Nephrol 8: 59–66, January, 2013

Glomerular Hyperfiltration in Hypertension, Palatini et al.

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differences in categorical variables was assessed with the chi-squared test. To explore the predictors of final AER, multivariable linear regression analyses were performed with final AER as the dependent variable and risk factors measured at baseline or their changes from baseline to study end as the independent variables. Logistic regression analysis was used to assess the risk of microalbuminuria or hypertension needing treatment during the follow-up for the GFR groups, with the group 1 category (normo→normo) serving as the referent. A two-tailed probability value ,0.05 was considered significant. For all statistical analyses, AER was transformed logarithmically (base 10) owing to skewed distribution. Analyses were performed using Statistica (version 6; Stat Soft Inc, Tulsa, OK), Systat (version 11; SPSS Inc, Evanston, IL), and MedCalc (version 12; MedCalc Software, Mariakerke, Belgium) software.

Results At baseline, 79.8% of the participants had normal GFR and 20.2% had glomerular hyperfiltration. Baseline hyperfilterers were younger (31.669.3 versus 34.068.3 years; P,0.001), were heavier (27.364.3 versus 25.063.2 kg/ m2; P,0.001), were more frequently male (79.6% versus 70.3%; P=0.05), and had a higher clinic systolic BP (149.369.8 versus 145.9610.6 mmHg; P=0.002) compared with normofilterers. Of the 426 participants with normal GFR at baseline, 395 were normofilterers also at final measurement (normo→normo, group 1) and 31 were hyperfilterers (normo→hyper, group 2). Of the 108 participants with baseline glomerular hyperfiltration, 61 were still hyperfilterers at final examination (hyper→hyper, group 3), whereas 47 showed normal GFR (hyper→normo, group 4). Of the 442 normofiltering participants at final examination, 89.4% had normal GFR also at baseline, whereas 10.6% had former glomerular hyperfiltration. Characteristics of the Four Groups Baseline and final GFR in the four groups are shown in Figure 1 and follow-up changes in GFR are reported in Table 1. GFR was .60 ml/min per 1.73 m2 in all of the participants also at study end. At baseline, group 1 participants (normo→normo) were older, leaner, and had a lower clinic BP and heart rate than the other groups (Table 1). The proportion of men was similar in group 1 and group 4 (hyper→normo) participants and in these two groups it was smaller than in group 2 (normo→hyper) and group 3 (hyper→hyper). Parental hypertension, smoking, alcohol use, physical activity habits, serum glucose, total cholesterol and triglycerides, urea nitrogen, uric acid, urinary NE, and length of follow-up were similar in the four groups (Table 1). Urinary epinephrine was higher in group 4 participants than in group 1 or group 2 participants, whereas no significant differences were found between the other groups (Figure 2). During follow-up, a greater increase in 24-hour systolic BP, serum glucose, and triglycerides was observed in group 4 participants compared with group 1 participants (Figure 3). Differences were not significant for BMI and cholesterol. Hypertension needing treatment was developed more frequently by participants in groups 2–4 than by group 1 participants (Table 1).

Figure 1. | GFR at baseline and at study end in 534 HARVEST participants grouped according to GFR changes during follow-up. Data are means and upper 95% confidence intervals. HARVEST, Hypertension and Ambulatory Recording Venetia Study; Nor→Nor, normofilterers throughout the study; Nor→Hyp, normofilterers at baseline and hyperfilterers at study end; Hyp→Hyp, hyperfilterers throughout the study; Hyp→Nor, hyperfilterers at baseline and normofilterers at study end.

Urinary Albumin At baseline, log-AER was lower in group 1 participants than in the other groups (Table 1). The log-AER values in the four groups at follow-up end are shown in Figure 4. AER was progressively higher on going from group 1 (median 6.8; IQR, 4.2–10.6 mg/24 h) to group 4 (median, 9.2; IQR, 7.5–27.6 mg/24 h). The P value for trend was also highly significant when data were adjusted for baseline log-AER. In a linear regression analysis independent predictors of final log-AER were GFR group (four-level variable), baseline log-AER, BMI, baseline mean 24-hour systolic BP, follow-up change in 24-hour systolic BP, and time elapsed between baseline and final measurements (Table 2). Mean 24-hour diastolic BP, clinic BP, parental hypertension, and lifestyle factors were not associated with the final level of AER. During the follow-up, 51 participants developed microalbuminuria. The incidence of microalbuminuria was progressively higher on going from group 1 (5.3%) to group 4 (36.2%) (Figure 4). Compared with group 1, the risk of microalbuminuria was increased significantly in groups 3 and 4 in both the univariate and the multivariable models in which changes in 24-hour BP over time were also included (Table 3). In group 4 participants, a 6.8-fold increase in the adjusted risk of microalbuminuria was found compared with group 1 participants. In sex-specific analyses, the GFR group–microalbuminuria relationship was statistically significant in both sexes. The adjusted risks of microalbuminuria for group 4 versus group 1 participants were 8.6 (95% confidence interval, 3.0–24.8; P,0.001) in men and 5.4 (95% CI, 1.1–26.2; P=0.04) in women.

Discussion The present longitudinal results obtained in initially normoalbuminuric hypertensive participants showed that

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Table 1. Baseline characteristics of the 534 participants divided according to GFR changes over 8.5 years of observation

Variable Male sex Parental hypertension Cigarette smokers Alcohol drinkers Physically active participants Age (yr) Body mass index (kg/m2) Clinic systolic BP (mmHg) Clinic diastolic BP (mmHg) Clinic heart rate (bpm) Mean 24-h systolic BP (mmHg) Mean 24-h diastolic BP(mmHg) Urea nitrogen (mmol/L) Uric acid (mmol/L) Glucose (mmol/L) Total cholesterol (mmol/L) Triglycerides (mmol/L) Log albumin excretion rate (mg/24 h) Urinary NE (mg/24 h) (n=360) Length of follow-up (d) Change in creatinine clearance (ml/min per 1.73 m2) Frequency of hypertension needing treatment (%)

Normo→Normo Group 1 (n=395)

Normo→Hyper Group 2 (n=31)

Hyper→Hyper Group 3 (n=61)

Hyper→Normo Group 4 (n=47)

273 (69.1) 247 (62.5)

27 (87.1) 18 (58.1)

54 (88.5) 34 (55.7)

32 (68.1) 26 (55.3)

0.003a 0.72a

71 (18.0) 190 (48.1) 125 (31.6)

5 (16.1) 15 (48.4) 11 (35.5)

10 (16.4) 26 (42.6) 16 (26.2)

8 (17.0) 23 (48.9) 19 (40.4)

0.71a 0.87a 0.74a

34.768.2 24.863.2

33.068.6 26.762.9

29.369.7 28.564.6

33.268.4 25.863.3

,0.001a ,0.001

145.5610.4

150.6611.8

148.9610.7

149.868.6

0.001

93.965.0

94.865.5

93.465.0

94.664.6

0.17

74.969.3

76.567.1

74.9610.2

78.1612.5

0.04

129.8611.3

130.5610.8

131.6610.4

132.2611.4

0.16

81.467.9

81.669.3

81.967.2

80.767.9

0.61

5.4661.68

5.4661.28

5.5361.41

5.8961.38

0.33

0.3060.08 5.2060.62 5.1761.02

0.2760.08 5.1560.47 5.4561.03

0.3160.06 5.2160.72 4.9460.89

0.3060.07 5.2260.49 4.9961.00

0.21 0.96 0.06

1.07 (0.75–1.49)

1.23 (1.06–1.52)

1.09 (0.85–1.43)

0.99 (0.73–1.58)

0.23b

0.6660.41

0.7960.50

0.8060.41

0.7660.52

0.04

90.6674.4

74.6636.9

108.1692.6

99.8683.3

0.19

2845 (1925–3800)

3080 (1600–4202)

2895 (2297–3767)

3049 (2219–3949)

0.26b

63.1698.9

27.9636.8

262.1651.1

70.9

68.4

68.6

0.2616.3 51.8

P Value

,0.001 0.004c

Data are n (%), mean 6 SD, or median (interquartile range) unless otherwise specified. P values for continuous variables are from ANCOVA for differences across groups and are adjusted for age and sex. Normo→normo, normofilterers throughout the study; normo→hyper, normofilterers at baseline and hyperfilterers at study end; hyper→hyper, hyperfilterers throughout the study; hyper→normo, hyperfilterers at baseline and normofilterers at study end. a Unadjusted. b P value from Kruskal–Wallis test. c P value from logistic regression analysis adjusting for age, sex, and baseline BP.

glomerular hyperfiltration at the baseline was associated with a higher final adjusted AER level and a more frequent development of microalbuminuria during the follow-up. The hyperfiltering participants who became normofilterers after 8.5 years had the highest risk of microalbuminuria. These associations also held true when both baseline 24hour systolic BP and ambulatory BP changes during follow-up were taken into account. These data suggest that the association between GFR and renal damage

follows a biphasic pattern in hypertension similar to the widely known biphasic pattern in renal function as observed in diabetes (15,16). The biphasic temporal relationship between GFR and urinary albumin can be inferred from Figure 4, in which a progressive increase in AER and microalbuminuria is shown on going from group 1 (normo→normo) to group 4 (hyper→normo). These data were obtained in a population-based cohort of nevertreated participants followed from diagnosis of hypertension,


Figure 2. | Twenty-four–hour urinary epinephrine in 360 HARVEST participants grouped according to GFR changes during follow-up. Data are means and upper 95% confidence intervals. P values are adjusted for age, sex, and body mass index. *P,0.001 versus Hyp→Nor; †P=0.02 versus Hyp→Nor. HARVEST, Hypertension and Ambulatory Recording Venetia Study; Nor→Nor, normofilterers throughout the study; Nor→Hyp, normofilterers at baseline and hyperfilterers at study end; Hyp→Hyp, hyperfilterers throughout the study; Hyp→Nor, hyperfilterers at baseline and normofilterers at study end.

making this a true natural history study. To our knowledge, no previous human studies have shown that hypertensive participants with normal GFR who had former hyperfiltration have a marked increase in the risk of microalbuminuria. Glomerular hyperfiltration is hypothesized to be a precursor of increased glomerular capillary pressure and is a proposed mechanism for microalbuminuria and renal injury in several clinical conditions (1,2,4,17). According to this view, GFR then falls progressively in parallel with a further rise in albuminuria, which may lead to progressive glomerulosclerosis, nephron loss, and ultimately to renal dysfunction (1,2). A recent meta-analysis has shown that the large majority of type 1 diabetic participants with glomerular hyperfiltration are at increased risk for albuminuria and the progression of diabetic nephropathy (4). Some studies suggest that this pathogenetic mechanism may also be operative in the early stage of hypertension (3,5,18). However, this sequence of events is difficult to study in humans because of the inability to obtain data over a long period of time without the confounding effect of therapy. In this study, the risk for microalbuminuria in the absence of glomerular hyperfiltration at baseline was minimal, suggesting that in the early stage of hypertension glomerular hyperfiltration is a potential precursor of renal damage. Predicting changes in AER in individuals with normal GFR is much more difficult. In the majority of participants, normofiltration represents a state of preserved renal function. However, some normofilterers may represent a group of former hyperfilterers who are assessed at a time when GFR has declined to within the normal range. Microalbuminuria was present in only 5% of our participants with normal filtration throughout the study, a proportion similar to that previously observed in normotensive individuals of


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similar age (19). In contrast, microalbuminuria was developed by over one-third of normofilterers with former hyperfiltration and participants in this group were not older than those who remained normofilterers throughout the study. These findings suggest that for glomerular hyperfiltration to develop in hypertension, the concomitant action of a variety of pathogenetic factors is needed. Our group 4 participants had a greater increase in 24-hour BP during the follow-up and a worsening of the metabolic profile compared with group 1 participants. Recent results obtained by Li et al. in a swine model showed that increased GFR is present in the early stage of the metabolic syndrome and is associated with renal adiposity and microvascular proliferation mainly of the renal cortex (20). In a large cohort of young men, glomerular hyperfiltration was shown to be associated with elevated BMI and an unfavorable metabolic profile (17). Sympatho-adrenergic activation may also contribute to the initiation and/or exacerbation of renal dysfunction (21). In our group 4 participants, we found increased clinic heart rate and elevated 24-hour urinary epinephrine concentration compared with group 1 individuals. Excessive adrenergic tone causes an increase in renal plasma flow and single nephron perfusion, with a subsequent rise in glomerular intracapillary pressure. This may lead to progressive GFR decline over time (22). In healthy participants, a moderate adrenergic stimulation causes renal vasoconstriction, which protects the glomerulus from the transmission of a high systemic pressure (22). This mechanism may be abolished in hypertensive patients (23), which may account for the decline in GFR found in our originally hyperfiltering participants. Several other mechanisms not explored in this study may contribute to development of renal dysfunction in participants with glomerular hyperfiltration. Activation of the renin-angiotensin-aldosterone system, increased oxidative stress, inflammatory cytokines, h-C-reactive protein, adipokines, and circulating free fatty acids have been associated with glomerular hyperfiltration and renal injury (2,24–26). Several shortcomings of our study have to be acknowledged. In this study, we have no information on GFR before baseline. It is thus impossible to exclude that some of the normofiltering participants included in group 1 were in the descending phase of the parabolic GFR pattern. However, in group 1 participants, mean GFR was almost identical at the beginning and at the end of the study and in no participant did GFR decline below the 60 ml/min per 1.73 m2 threshold. In addition, the very low incidence of microalbuminuria in this group argues against possible misclassification. Another limitation is that we used creatinine clearance to measure GFR, which tends to overestimate the real GFR compared with inulin clearance or radioisotopic techniques (27). However, overestimation of GFR occurs especially at low levels of renal function (28) and none of our patients had a GFR ,60 ml/min per 1.73 m2. In addition, accurate timing ensured a complete 24-hour urine collection, which took place during the 24-hour ambulatory monitoring under the supervision of healthcare personnel as reported previously (29). Another possible limitation is that we did not control for protein intake that is known to affect GFR (30). However, our data were obtained from a homogeneous cohort of people with

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Figure 3. | Follow-up changes in mean 24-hour systolic BP, serum glucose, triglycerides, and total cholesterol, in 534 HARVEST participants grouped according to GFR changes during follow-up. Group 1 indicates normofilterers throughout the study; group 2, normofilterers at baseline and hyperfilterers at study end; group 3, hyperfilterers throughout the study; and group 4, hyperfilterers at baseline and normofilterers at study end. Data are means and upper 95% confidence intervals. P values are adjusted for age, sex, and baseline level. §P=0.01 versus group 1; ¶ P=0.002 versus group 1; ‡P=0.001 versus group 1. HARVEST, Hypertension and Ambulatory Recording Venetia Study.

Figure 4. | AER level and incidence of microalbuminuria at study end. (Left Panel) Logarithm of AER at study end in 534 HARVEST participants grouped according to GFR changes during follow-up. Group 1 indicates normofilterers throughout the study; group 2, normofilterers at baseline and hyperfilterers at study end; group 3, hyperfilterers throughout the study; and group 4, hyperfilterers at baseline and normofilterers at study end. Data are means and upper 95% confidence intervals. P value for trend adjusted for age, sex, and baseline urinary albumin (P,0.001). (Right Panel) Incidence of microalbuminuria at study end in the four groups. Data are proportions and upper 95% confidence intervals (x 2=48.4; P,0.001). AER, albumin excretion rate; HARVEST, Hypertension and Ambulatory Recording Venetia Study.



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Table 2. Significant predictors of albumin excretion rate (log transformed) at final assessment: Summary of multiple regression analyses

Variable

b-Coefficient

SEM

P Value

GFR group Log albumin excretion rate, baseline (mg/24 h) 24-h systolic BP, baseline (mmHg) 24-h systolic BP, change (mmHg) Time to final assessment (d) Sex (female) Body mass index (kg/m2) Parental hypertension (yes/no) Smoking (yes/no) Alcohol use (yes/no) Physical activity (yes/no) Clinic systolic BP, baseline (mmHg) Clinic diastolic BP, baseline (mmHg) 24-h diastolic BP, baseline (mmHg) Age (yr) 24-h diastolic BP, change (mmHg)

0.085 0.145 0.006 0.005 0.007 0.082 0.012 0.027 0.011 20.051 0.024 20.003 0.004 0.001 0.002 0.001

0.019 0.046 0.002 0.002 0.002 0.046 0.006 0.028 0.022 0.030 0.021 0.002 0.004 0.004 0.002 0.003

,0.001 0.002 0.004 0.03 ,0.001 0.07 0.04 0.33 0.61 0.10 0.26 0.10 0.31 0.75 0.36 0.84

Multiple R=0.38. Multiple R2=0.14.

Table 3. GFR group as predictor of microalbuminuria at study end

Model Univariate Group 1 (normo→normo)a Group 2 (normo→hyper) Group 3 (hyper→hyper) Group 4 (hyper→normo) Multivariate Group 1 (normo→normo)a Group 2 (normo→hyper) Group 3 (hyper→hyper) Group 4 (hyper→normo)

OR

95% CI

P Value

1.0

–

–

1.9

0.5–6.8

0.32

3.5

1.6–7.8

0.002

10.1

4.8–21.1

,0.001

1.0

–

–

1.6

0.4–6.9

0.50

3.0

1.1–7.9

0.03

7.8

3.3–18.2

,0.001

The multivariate model was adjusted for albumin excretion rate at baseline, age, sex, mean 24-hour systolic and diastolic BP, mean 24-hour heart rate, clinic systolic BP, clinic diastolic BP, BMI, parental hypertension, lifestyle factors, time to final assessment, and changes in 24-hour BP. OR, odds ratio; CI, confidence interval; normo→normo, normofilterers throughout the study; normo→hyper, normofilterers at baseline and hyperfilterers at study end; hyper→hyper, hyperfilterers throughout the study; hyper→normo, hyperfilterers at baseline and normofilterers at study end. a This served as the reference category.

similar dietary habits, and BUN and uric acid, two surrogate markers of protein intake (30), did not differ between the four GFR groups. Finally, the number of participants who developed microalbuminuria was relatively modest.

However, the progressive increase in AER across the four GFR groups confirms the results obtained with the categorical classification. According to current guidelines, only low GFR and microalbuminuria or proteinuria are considered markers of reduced renal function (13). Up to now, glomerular hyperfiltration has not been included among the risk factors for renal dysfunction. However, considering the strong association between glomerular hyperfiltration and risk for development of microalbuminuria shown in this study, glomerular hyperfiltration should be regarded as a precursor of nephropathy in hypertension. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers proved highly effective in decreasing glomerular hypertension in experimental models of renal injury (31,32) and it has been demonstrated that reverting glomerular pressure to normal delays renal dysfunction, despite persistence of hyperfiltration (33). Renin-angiotensin-aldosterone system inhibition appears particularly useful in hypertensive participants with hyperadrenergic activity because it may restore the physiologic renal hemodynamic response to adrenergic activation (23). Our findings suggest that intervention to reduce GFR might benefit young hypertensive participants who hyperfiltrate, even before the onset of microalbuminuria. However, confirmation of this hypothesis would require randomized, controlled trials. Acknowledgments This study was funded by the University of Padova, Padova, Italy, and by the Associazione “18 Maggio 1370”, San Daniele del Friuli, Italy. Disclosures None. References 1. Brenner BM, Lawler EV, Mackenzie HS: The hyperfiltration theory: A paradigm shift in nephrology. Kidney Int 49: 1774–1777, 1996

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Received: April 6, 2012 Accepted: August 3, 2012 Published online ahead of print. Publication date available at www. cjasn.org.