1 Medical Clinic IV Department of Nephrology and 2 Medical Clinic III Department of Infectious Disease, J.W. Goethe University, Frankfurt/Main, Germany
Correspondence and offprint requests to: Dr Oliver Jung, Klinikum der Johann Wolfgang Goethe-Universität, Medizinische Klinik IV, Funktionsbereich Nephrologie, D-60590 Frankfurt/Main, Germany. Email: jung{at}zphys1.uni-frankfurt.de The authors wish it to be known that, in their opinion, the first two authors contributed equally to this work.
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Abstract |
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Methods. In this prospective study, HIV-1-infected patients from the Frankfurt AIDS Cohort Study (FACS) were followed for 1 year to determine the frequency of systemic hypertension and to assess the associated clinical and demographic factors.
Results. A total 214 HIV-1-infected patients, predominantly Caucasian males, participated in the study. Prevalence of systemic hypertension was 29%. The groups of hypertensive and normotensive individuals were comparable in terms of ethnic background and duration of infection. As in the general population, hypertensive subjects were older (49.1±11.1 vs 39.0±8.1 years; P<0.0001) and waist-to-hip ratio was higher than in normotensive individuals (0.99±0.07 vs 0.93±0.08; P<0.0001). Hypertension was associated with a much higher frequency of persistent proteinuria (41.1% vs 2.8%; P<0.001), coronary heart disease (16.1% vs 1.3%; P<0.0001) and myocardial infarction (8.1% vs 0.7%; P<0.005), whereas most cardiovascular risk factors were similar in both groups.
Conclusions. Our data do not demonstrate any association between the presence of hypertension and antiretroviral therapy or immune status. However, hypertension seems to have a high impact on the existing risk for premature cardiovascular disease. Furthermore, overt proteinuria is frequent in HIV-1 infection with hypertension and might be due to hypertensive nephrosclerosis as well as yet undefined renal disease in these patients.
Keywords: cardiovascular disease; HIV; hypertension; proteinuria
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Introduction |
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However, metabolic disorders, such as hyperlipidaemia, impaired glucose tolerance and body shape changes, like visceral fat accumulation (lipodystrophy syndrome), are frequently associated with the use of HAART [2]. As these metabolic complications may lead to premature and accelerated atherosclerosis, there is growing concern that cardiovascular disease is becoming more prevalent in this population [3]. Specific treatment of these problems will become increasingly important to further decrease long-term morbidity and premature mortality in HIV-1-infected patients.
Hypertension is one of the major risk factors for premature cardiovascular disease. While metabolic disorders are frequently seen in HIV-positive patients under HAART, an association with hypertension has not been clearly identified yet and sufficient data on the prevalence of hypertension in the HIV-1-infected population are still lacking.
While systemic hypertension was quite uncommon in HIV-1-infected subjects prior to HAART [4], newer data suggest that younger HIV-1-infected patients are at a higher risk for developing hypertension compared with the general population, especially if a protease inhibitor was included in the HAART regimen [58].
The purpose of our study was to evaluate the frequency of systemic hypertension in a cohort of HIV-infected individuals and to examine the effect of chronic HIV infection, chronic antiretroviral therapy and traditional risk factors on systemic blood pressure and to assess the impact of hypertension on cardiovascular comorbidity in this population.
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Subjects and methods |
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Patients were recruited after informed consent was obtained during the initial routine clinical visit. Patients were then prospectively followed up for 1215 months.
Information on medication, age, ethnic background, HIV infection, concomitant diseases or complicating conditions was assessed by history, computerized patient database, review of medical records and physical examination.
Myocardial infarction was diagnosed on the basis of clear-cut evidence, such as documented earlier events with electrocardiogram and enzyme determinations or coronary angiography showing myocardial infarction. Coronary artery disease was defined as angina pectoris requiring antianginal medications or when documented by previous coronary angiography. Stroke was assessed on the basis of physical examination or when documented by cranial computerized tomography or magnetic resonance imaging in the patient's previous medical record. Peripheral occlusive vascular disease was assessed historically in terms of previous operations, clinically in terms of claudication by physical examination or by the appropriate non-invasive or invasive methods. Diabetes was defined as fasting blood glucose >126 mg/dl in at least two office visits, when documented in the medical record or by the use of oral antidiabetics or insulin.
A standardized questionnaire was used to evaluate patterns of lifestyle, family history for hypertension and cardiovascular disease in a first-degree relative and to ask for signs of body shape changes (lipodystrophy). These changes were scored as absent or present with regard to facial fat loss, increased neck fat (anterior or posterior), increased trunk or chest fat and decreased leg and arm fat. Patients were categorized as having primary lipoatrophy (with no evidence of increased abdominal fat), primary lipohypertrophy (increased abdominal fat with or without increased neck fat and no evidence of peripheral fat atrophy) or mixed lipodystrophy (presenting with both increased abdominal fat and peripheral fat atrophy).
Vital signs obtained included height, body weight, measurement of waist and hip circumference for determination of waist-to-hip ratio (WHR) and body mass index (BMI) as defined by the WHO.
Clinic blood pressure measurement
Blood pressure was measured non-invasively at all visits with a mercury column sphygmomanometer [first and fifth phases of Korotkoff sounds taken as systolic (SBP) and diastolic blood pressure (DBP), respectively] after the subjects had rested for 510 min in the sitting position. The consecutive measurements were done 2 min apart.
Patients untreated for systemic hypertension showing DBP values of 90 mmHg and/or SBP values of
140 mmHg in two or more office visits over
3 months as well as patients with treated hypertension, irrespective of blood pressure values during the study period, were regarded as hypertensive according to WHO/ISH guidelines definition.
Laboratory tests
Blood and urine samples for routine chemistries were obtained at every visit of the follow-up period. Routine laboratory tests included serum creatinine, serum urea, serum uric acid, fasting serum glucose, total, high-density lipoprotein- and low-density lipoproteincholesterol and triglycerides. CD4 T-lymphocyte count was determined by flow cytometry. HIV viral load was measured using quantitative polymerase chain reaction assay (Roche Amplicor; Roche Diagnostics GmbH, Mannheim, Germany) and was reported as copies of free RNA/ml, with a lower limit of detection of 400 copies/ml (or 50 copies/ml when using the ultrasensitive assay).
Persistent proteinuria was defined when at least two consecutive positive dipstick tests (>1+) were obtained during follow-up. Factors associated with false/transient positive dipstick for proteinuria were examined and results positive for proteinuria in subjects with fever (>98.6°F), significant haematuria, leukocyturia or highly alkaline urine (pH>7.5) were not included into the study.
Additionally, patients with persistent proteinuria were asked to submit 24 h urine collections for quantification of total proteinuria and determination of patterns of urinary proteins by quantitative computerized nephelometry. Proteinuria was classified depending on the molecular weight, urinary excretion and selectivity into the following subtypes: overflow proteinuria, tubular proteinuria (caused by tubular dysfunction) and glomerular proteinuria (selective and non-selective glomerular proteinuria).
Antiretroviral therapy
Evaluation of antiretroviral therapy was done for current therapy and for cumulative duration of therapy.
Current antiretroviral therapy, defined as medication at the last visit of follow-up, was coded in three different ways. First, medications were coded for any specific antiretroviral agent. Second, these medications were coded based on their drug class (NRTI: nucleoside reverse transcriptase inhibitors; NNRTI: non-nucleoside reverse transcriptase inhibitors; or PI: protease inhibitors). Third, medication was categorized by the combination regimes: (i) 2 NRTI + 1 PI, (ii) 2 NRTI + 2 PI, (iii) 2 NRTI + 1 NNRTI, (iv) 3 NRTI and (v) double PI.
Cumulative duration of antiretroviral therapy was coded in two different ways. First, medications were coded for any specific antiretroviral agent administered ever to the patients from the first initiation of antiretroviral therapy until the end of the follow-up. Second, duration of different regimens of antiretroviral in each participant was coded based on the following categories: (I) mononucleoside reverse transcriptase inhibitor therapy, (II) dual nucleoside reverse transcriptase inhibitor therapy and (III) HAART (more than two antiretroviral agents, including at least one PI or one NNRTI).
Statistical methods
Demographic, clinical and laboratory parameters were described for the patient cohort overall and for groups of patients defined by the presence or absence of systemic hypertension. Continuous variables are expressed as means±SD.
Categorical and continuous variables were compared for univariate analysis between groups using the KruskalWallis test and Chi-square test, respectively. All P-values reported are two-sided and all confidence intervals (CI) are 95% intervals. Statistical significance was defined as P 0.05.
The associations between the presence of hypertension and demographic, clinical and laboratory variables were estimated by stepwise multivariable logistic regression [odds ratio (OR) and 95% CI].
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Results |
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Diagnosis of hypertension was known for 5.9±6.6 years. Thirty-three subjects (53.2% of hypertensives) received antihypertensive therapy during the study period. While 28 patients already had antihypertensive treatment prior to study entry, five patients were started on antihypertensive therapy during the follow-up. Seventeen patients received mono, 13 patients dual, two patients triple and one patient quadruple therapy. Diuretics were used in 10 patients, ß-blockers in 19, angiotensin-converting enzyme inhibitors in seven, angiotensin receptor blockers in nine, calcium channel blockers in four and an 1-blocker in one.
Comparison of demographic and clinical data between hypertensive and normotensive patients
The mean SBP in the hypertensive group at study entry was 139.7±14.9 mmHg and the mean DBP was 88.2±9.7 mmHg compared with 122.1±13.5 and 77.8±8.9 mmHg in the normotensive group, respectively (P<0.0001). At the end of follow-up, SBP was 137.5±1.9 mmHg and DBP was 86.7±1.2 mmHg in the hypertensive group as compared with 118.9±1.2 and 76.6±8.7 mmHg in the normotensive group, respectively (P<0.0001).
Table 2 provides a comparison of the demographic and clinical features. With a few exceptions, the two groups were comparable. First, the hypertensive group was an average of 10 years older than the normotensive group (49.4±11.1 vs 39.0±8.1 years; P<0.0001). Accordingly, age >50 years was associated with a >7-fold increased risk of having hypertension (OR: 7.77; 95% CI: 3.4117.73; P<0.0001).
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A WHR 1 was associated with an increased risk for hypertension (OR: 2.45; 95% CI: 1.105.46; P<0.05), whereas a BMI of >25 was not significantly associated with hypertension (OR: 1.36; 95% CI: 0.622.96; P = 0.45) in multivariate analysis. No significant difference was observed between hypertensive and normotensive subjects in terms of ethnic background and risk factor for HIV acquisition.
Comparison of risk factors for systemic hypertension, family history and concomitant cardiovascular disease
The hypertensive and the normotensive group were comparable in terms of lifestyle-dependent risk factors for cardiovascular disease and hypertension, such as smoking, sports and alcohol consumption (Table 3).
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Prevalence of diabetes mellitus was higher in the hypertensive group compared with the normotensive group, but this difference did not reach statistical significance (8.1% vs 2.6%; P = 0.08).
Despite comparable family history and frequency of diabetes mellitus, the proportion of patients with concomitant coronary heart disease and medical history of myocardial infarction was >10-fold higher in hypertensive individuals than in the normotensive group (for coronary heart disease 16.1% vs 1.3% and for myocardial infarction 8.1% vs 0.7%; P<0.0001 and P<0.005, respectively). Furthermore, patients with systemic hypertension were more likely to have a medical history for stroke (3.2% vs 0%; P<0.05) and peripheral occlusive vascular disease (6.5% vs 0%; P<0.01) than those with normotension.
While WHR was significantly higher in hypertensive patients, frequency of body shape changes (lipodystrophy) was not increased as compared with normotensive patients.
No significant differences were observed in frequency of chronic infection with hepatitis B or C.
Comparison of patterns of HIV infection and antiretroviral therapy
There was no difference between hypertensive and normotensive individuals in the duration of diagnosed HIV infection and proportion of patients with AIDS. Since mean HIV-RNA levels and mean CD4 lymphocyte counts did not change significantly within the groups during the time course of the study, only data from the end of the follow-up period are presented in Table 4. Whereas HIV-RNA levels did not differ between the two groups, mean CD4 lymphocyte counts were slightly lower in the hypertensive individuals than in the normotensive group (418±200 vs 499±265 cells/mm3; P<0.05). Moreover, cumulative duration of antiretroviral therapy was longer in hypertensive patients as compared with normotensive patients (61.7±28.8 and 51.0±24.6 months; P<0.01).
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Comparison of laboratory tests
No significant changes in the mean values for metabolic and renal parameters in the two groups were noted over the time course. Thus, values for these parameters were reported only for the end of follow-up (Table 5).
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Fasting serum triglycerides were significantly higher in the hypertensive group (274±22 vs 216±14 mg/dl; P<0.05). Uric acid was elevated in the hypertensive as compared with the normotensive group (7.12±0.54 vs 5.71±0.34 mg/dl; P<0.05), although the use of uricosurics tended to be even higher in the hypertensive group.
Mean serum creatinine was similar in both groups. Two or more consecutive dipstick tests per individual were obtained in 204 patients. Prevalence of a persistent proteinuria was tremendously higher in the hypertensive as compared with the normotensive group (41.1% vs 2.8%; P<0.0001).
Associations with persistent proteinuria
Because of the unexpected high prevalence of persistent proteinuria in the hypertensive group, further statistical evaluation on factors associated with proteinuria was performed and patients with persistent proteinuria were asked to submit 24 h urine collections for quantification and classification of total proteinuria. The mean urinary protein excretion in the 23 hypertensive patients with persistent proteinuria was 1045 mg/day, with a range from 254 to 6400 mg/day. Five of these patients had proteinuria of >2000 mg/day, three had a proteinuria between 1000 and 2000 mg/day and 15 had a proteinuria <1000 mg/day.
Proteinuria was classified as glomerular proteinuria in all 23 hypertensive patients with proteinuria. Eighteen patients had selective glomerular proteinuria and five had non-selective glomerular proteinuria. All patients with non-selective glomerular proteinuria had a total proteinuria of >2000 mg/day.
A urinary protein excretion rate >1000 mg/day (range: 178688 mg/day) was not observed in any of the four normotensive patients with persistent proteinuria. Two of these patients had tubular proteinuria, one had selective glomerular proteinuria and one had non-selective glomerular proteinuria.
Patients with (n = 27) and without (n = 177) persistent proteinuria were similar in most parameters evaluated in the study (data not shown). Significant differences observed included that patients with proteinuria were older (50.8±11.3 vs 40.8±9.4 years; P<0.0001), had a higher WHR (0.99±0.07 vs 0.94±0.08; P<0.01) and were more likely to have hypertension (85.2% vs 2.3%; P<0.0001), diabetes mellitus (14.8% vs 2.8%; P<0.01) as well as coronary heart disease (14.8% vs 4.0%; P<0.01). Additionally, cumulative duration of antiretroviral therapy was longer in these patients (65.6±25.7 vs 51.7±25.3 months; P<0.01). Factors associated with impairment of renal function, such as co-infection with hepatitis B or C, serum creatinine and medical history of indinavir nephropathy, also did not differ between the groups.
Nevertheless, hypertension was the only predictor of persistent proteinuria using stepwise multivariable logistic regression (OR: 19.60; 95% CI: 5.7466.99; P = 0.0001).
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Discussion |
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Systemic hypertension was present in 29% of HIV-infected patients in our cohort (age range: 2174 years). Groups of hypertensive and normotensive patients were comparable in terms of ethnic background, risk factor for HIV, proportion of AIDS and duration of infection, but patients with systemic hypertension had lowered CD4 lymphocyte counts and longer cumulative duration of antiretroviral therapy.
As in the general population, hypertensive subjects were older and BMI and WHR were higher compared with normotensive patients. Moreover, age and WHR were found to be independent risk factors for the development of hypertension in this population. In contrast, BMI was found not to be an independent risk factor, as changes in BMI observed in the cohort might be attributable to the age-related increase in body weight.
The hypothesis of an increased risk for the development of hypertension in HIV-infected patients is based mainly on a few studies investigating the effects of PIs, in particular with regard to indinavir, and lipodystrophy on blood pressure as well as on observational data [58].
The largest study performed on this topic is a retrospective database analysis of 2032 patients, demonstrating an increase in SBP and DBP of <4 mmHg in patients receiving PI or NNRTI as compared with those without antiretroviral therapy [6]. However, no additional parameters affecting level of blood pressure, such as comorbidity, side medications, traditional risk factors, etc., were available. Moreover, data might be influenced by including blood pressure measurements pre-dating HAART into this comparison, when HIV-infected patients tended to have lower blood pressure than the general population because of their lowered health state [4].
Another retrospective study showed a significant increase in SBP and DBP in patients under long-term therapy with indinavir in comparison to baseline blood pressure prior to PI therapy [7]. Additionally, none of the patients in the HIV-infected control group but 29% of patients in the indinavir-treated group experienced systemic hypertension. Apart from age, groups were not matched or compared for traditional risk factors of hypertension, which is of note, as the majority of patients developing hypertension in the indinavir-treated group had positive family history, but respective data were not collected in the normotensive patients of the indinavir-treated group and the control group.
In contrast to these findings, a recently published study showed a lower prevalence of hypertension in HIV-1-infected patients receiving PI-containing regimen compared with age-matched HIV-1-uninfected subjects from the WHOMONICA Project [9].
In our study, we observed no statistical difference between hypertensive and normotensive patients when comparing current as well as total duration of specific antiretroviral drugs or combination regimen. However, as 18 different antiretroviral agents are available for the combination therapy of HIV disease, the number of patients in our study might be too small to show significant differences in regards to specific antiretroviral drugs. Moreover, 59% of our patients were treated with indinavir prior to study entry, but only 10% received indinavir during the study period. Our results, therefore, do not argue against the observation made by Cattelan et al. [7], as hypertension completely recovered after withdrawal of indinavir in almost 50% of their cases.
Nevertheless, cumulative duration of antiretroviral therapy was longer in the hypertensive group as compared with the normotensive group.
However, this observation should be interpreted carefully. We also observed lower CD4 lymphocyte counts in hypertensive patients. This might be attributable to the higher mean age in the hypertensive group, as CD4 lymphocyte counts lower with age and recovery of CD4 cells in response to antiretroviral therapy is impaired in older subjects, making a more intensive antiretroviral therapy necessary [10]. Indeed, when the analysis was adjusted for age, no difference in CD4 cell counts and cumulative duration of antiretroviral therapy was found. Thus, it is difficult to establish a clear link between antiretroviral therapy or immune status and hypertension from our data.
A retrospective case-control study on 84 HIV-positive patients showed an association between lipodystrophy and elevated blood pressure [8]. But patients with lipodystrophy were older and when data were controlled for family history of hypertension the difference in blood pressure tended to diminish. Moreover, WHR did not differ between HIV patients with and without lipodystrophy, with almost half of the control group meeting criteria for abdominal obesity. In addition, the authors demonstrated a correlation between WHR as well as serum triglycerides and blood pressure elevation. These findings are consistent with those of another group and our observations showing higher WHR, elevated triglycerides and uric acid in hypertensive as compared with normotensive patients [5].
In contrast to these previous studies [5,8], we observed no difference in proportions of patients with lipodystrophy, comparing hypertensive to normotensive HIV-infected groups, but interpretation of results is limited as to date there is no clear-cut definition for the diagnosis of lipodystrophy.
Taking these findings together, it appears questionable that antiretroviral therapy has a significant direct impact on blood pressure. Effects on blood pressure may be small or affect only a small number of susceptible patients, as proposed by others [5,7].
In our study, HIV-1-infected patients with systemic hypertension were much more likely to suffer from cardiovascular disease, while most other traditional risk factors for cardiovascular disease were comparable between both groups, so that hypertension seems to have a high impact on the existing risk for premature cardiovascular disease in these patients [3].
Persistent proteinuria was present in 41.1% of the hypertensive group, but only in 2.8% of the normotensive group, while serum creatinine was in the normal range.
Our results in terms of persistent proteinuria in the normotensive group are concordant with prior studies showing a prevalence of 824% in non-Hispanic white patients not selected for hypertension [11,12]. Unexpectedly, persistent proteinuria, a marker for the presence of glomerular/renal disease, was present in 41.1% of the hypertensive group and, thus, almost 15 times more frequent than in the normotensive group. But, as 20% of all patients seen in this period at the FACS participated in this study, we cannot completely rule out that the results are influenced by a selection bias. It is conceivable, for whatever reason, that patients with more severe disease were more likely to enrol and that the high frequency of proteinuria observed may be an overestimate of its true prevalence.
Nevertheless, the frequency of proteinuria in these patients is even more remarkable when comparing our results with data from studies of proteinuria in non-infected patients with hypertension.
While microalbuminuria is frequently seen in hypertensive patients, overt proteinuria is more uncommon [13]. The prevalence of proteinuria in hypertensive patients varies from 3% to 16%, depending on population data, such as age, race and severity and duration of hypertension, and is, thus, abundantly lower when compared with the hypertensive HIV-infected patients in our study [14,15].
Our data do not allow the precise definition of the renal lesions causing proteinuria in our patients. Whether hypertension observed in our study cohort can be interpreted as cause or consequence of renal disease has yet to be determined.
As a variety of glomerular diseases occur more frequently in the HIV-seropositive population, the detection of proteinuria may be indicative of occult nephropathy [16]. It has been demonstrated that the high incidence of proteinuria in non-selected cohorts of HIV-infected patients is, in part, due to the high prevalence of chronic infection with hepatitis B or C and consecutive secondary renal involvement [12]. However, as the number of patients co-infected with hepatitis is low in our cohort (10% of the total population; 4.8% of the hypertensive group) this cannot explain this observation.
HIV-associated nephropathy (HIVAN) is the single most common cause of renal disease in HIV-seropositive patients [16]. The vast majority of patients are of black race, which might explain the observation that black race is a major risk factor for proteinuria in HIV infection [13]. Nevertheless, due to this racial distribution, incidence of HIVAN is low in most centres in Europe [16]. In our population, only 2.3% were of black race and none of them was in the hypertensive subgroup; thus, it seems unlikely that proteinuria in our hypertensive group might be attributable to occult HIVAN, even more as HIVAN is typically not associated with hypertension.
In individual cases, proteinuria may be attributable to diabetic nephropathy, since two hypertensive patients with proteinuria had concomitant diabetes mellitus.
Because of these considerations it appears questionable that the high incidence of overt proteinuria, with >40% of hypertensives being affected, can be attributed solely to be secondary to underlying renal disease, even more so as hypertension was the only predictor of persistent proteinuria.
Moreover, proteinuria in all hypertensive HIV-1-infected patients was of glomerular type, as 18 patients had selective and five had non-selective glomerular proteinuria. Therefore, it seems unlikely that tubular alterations, e.g. caused by interstitial nephritis, play an important role in the development of proteinuria in these patients. As proteinuria is attributable mainly to glomerular damage in this population, at least some common pathogenetic pathways may be involved, even if different causes of underlying renal diseases do exist, leading to the observed high frequency of overt proteinuria.
It is important to notice that direct infection of renal epithelial and tubular cells with HIV and active replication of the virus have been reported even in the absence of overt HIV-related renal disease and during successful therapy [17]. HIV-1-infected renal cells may increase synthesis of transforming growth factor-ß (TGF-ß), which is involved in the pathogenesis of several forms of progressive renal disease, by increased extracellular matrix synthesis and decreased degradation [18]. Additionally, HIV proteases might influence the reninangiotensin cascade and serum angiotensin-converting enzyme levels have been found to be elevated in patients with HIV infection [19].
This raises the possibility that renal disease in hypertensive patients may be related to undefined actions of the virus, i.e. an autoimmune process induced by HIV on renal cells, making them more susceptible for hypertensive damage leading to hypertensive nephrosclerosis and proteinuria or to be even more speculative to a yet undefined renal disease. Irrespective of whether hypertension is caused by renal disease in our cohort or vice versa, it is clear that hypertension is a major determinant of progression of renal disease and the risk of end-stage failure [20]. Furthermore, proteinuria is not only a marker for renal disease, but is also an independent risk factor for the development of chronic and progressive renal disease and for an increased incidence of cardiovascular morbidity and mortality [13].
Longitudinal follow-up and renal biopsy of patients with persistent proteinuria will be necessary to determine whether these develop overt renal disease.
Conflict of interest statement. None declared.
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