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NDT Advance Access published online on November 11, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn566
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Management and control of hypertension and proteinuria in patients with advanced chronic kidney disease under nephrologist care or not: data from the AVENIR study (AVantagE de la Néphroprotection dans l'Insuffisance Rénale)

Nathalie Thilly1, Stéphanie Boini1, Michèle Kessler2, Serge Briançon1 and Luc Frimat2

1 Department of Clinical Epidemiology and Evaluation, CEC-CIE6 Inserm, EA 4003, Nancy University, Nancy 2 Department of Nephrology, Brabois Hospital, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France

Correspondence and offprint requests to: Nathalie Thilly, Service d’Epidémiologie et Evaluation Cliniques, CHU Nancy, CO n°34, 54035 Nancy cedex, France. Tel: +33-03-83-85-21-63; Fax: +33-03-83-85-12-05; E-mail: n.thilly{at}chu-nancy.fr



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Little is known about antihypertensive management and control of blood pressure (BP) and proteinuria in patients with chronic kidney disease (CKD). Data from a large observational study (AVENIR), carried out in Lorraine (France), were used to analyse antihypertensive treatment and control of BP and proteinuria in patients with advanced CKD, under nephrologist care or not.

Methods. All adults with CKD, beginning dialysis in 2005 and 2006, were included and categorized into patients ‘under nephrologist care’ and ‘not under nephrologist care’ at the time when treatment, BP and proteinuria results were considered. All data were collected retrospectively from medical records. Demographic and clinical data were from initiation of dialysis. BP, biological and therapeutic data were results obtained at 2.7 months before dialysis for patients under nephrologist care, and results obtained at the first nephrology consultation for those not under such care (2.7 ± 3.7 months before dialysis).

Results. On 566 included patients, the 291 under nephrologist care received more antihypertensive agents (3.1 ± 1.5 versus 2.2 ± 1.6) than the 275 not under such care and each antihypertensive class was more often prescribed for these patients, particularly the renin–angiotensin–aldosteron system inhibitors (60.5% versus 36.7%). Nevertheless, BP did not differ between both groups, and proteinuria control was achieved in more patients not under nephrologist care, revealing a likely bias of indication. Whatever the type of care, BP < 130/80 mmHg was achieved in only one quarter of all patients and proteinuria < 0.5 g/day in only 15% of them.

Conclusion. Understanding the reasons for such a poor level of hypertension and proteinuria control in CKD patients needs to be explored in further investigations.

Keywords: chronic kidney disease; clinical practice guidelines; hypertension; nephrologist care; proteinuria



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
Chronic kidney disease (CKD) constitutes a highly prevalent heath problem worldwide. CKD patients are recognized to be at high risk for cardiovascular morbidity or mortality and end-stage renal disease (ESRD), which in turn aggravates cardiovascular conditions [1,2].

Hypertension is present in more than 80% of patients with CKD [3]. As either the cause or the consequence of CKD, hypertension contributes to progression of kidney disease towards ESRD as well as to cardiovascular events [4,5]. Furthermore, hypertension is often associated with proteinuria, which is itself an independent risk factor for CKD progression and cardiovascular events [6,7].

Evidence from observational cohort studies and randomized controlled trials emphasizes the importance of lowering blood pressure (BP) and proteinuria to delay the decline of kidney function and prevent cardiovascular mortality in CKD [8–10]. At present, guidelines recommend a BP goal of < 130/80 mmHg and a proteinuria goal of < 0.5 g/day for all CKD patients [11,12].

To achieve the BP goals, various antihypertensive therapies are available. Clinical trials have not shown differences between antihypertensive classes for reducing BP. Nevertheless, as well as lowering BP, antihypertensive agents can also have direct effects on intrarenal mechanisms of damage, such as increased proteinuria and glomerular pressure. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), which block the actions of the renin–angiotensin–aldosteron system (RAAS), are more effective than other antihypertensive regimens for reducing proteinuria [13]. Thus, their beneficial effects appear to be mediated by factors additional to their effects on BP. These RAAS inhibitors, now considered the gold standard in decreasing progression to ESRD and death [14,15], are thus recommended as a first line antihypertensive approach for CKD.

However, little is known about antihypertensive management and actual control of BP and proteinuria in patients with CKD. Few studies have examined this issue and seem to show that insufficient attention is paid to lowering BP [16–21]. Moreover, clinical guidelines are well known in the nephrology setting, but primary care physicians manage a high proportion of CKD patients, even at advanced stages, in most countries [22]. Now, it has been clearly shown that a delayed referral to nephrologists is associated with increased morbidity, longer hospital stays, and earlier mortality [23–25]. To what extent this increased morbi-mortality observed in late-referral patients is due to a worse control of hypertension and proteinuria is unknown. Unfortunately, within the current context, a controlled trial where patients would be randomized on timing of a referral is not conceivable for ethical reasons.

We therefore used data from the AVENIR (AVantagE de la Néphroprotection dans l’Insuffisance Rénale) observational study to investigate antihypertensive management and control of BP and proteinuria in early and intermediate or late referred CKD patients.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Setting
Lorraine is one of 22 administrative regions of metropolitan France. It is situated in the northeast of the country and has an urban and rural population of 2 339 000, according to the 2006 census. The AVENIR study involved 12 of the 13 private and public nephrology units operating in Lorraine.

Inclusion criteria and enrolment
AVENIR was designed to evaluate the consequences of therapeutic care delivered to pre-ESRD patients on their quality of life, and morbidity/mortality during the first year of dialysis treatment. Details of the study have been described elsewhere [26].

All adults with CKD, who began dialysis treatment in the 12 units involved between 1 January 2005 and 31 December 2006, were identified from the regional ESRD registry (REIN registry) and included in the study. Patients with reversible renal failure and those returning to dialysis following kidney graft failure were excluded.

Data collection and definitions
A standardized form was used to collect retrospectively demographic, clinical, biological and therapeutic data from outpatient medical records. Demographic and clinical data were from inclusion in the REIN registry, whereas biological and therapeutic data covered a time period from the day of the first nephrologist consultation to initiation of dialysis.

Referral was considered early when it took place more than 1 year before dialysis initiation (the mean referral time: 58.0 ± 55.7 months before dialysis) and intermediate to late less than 1 year (the mean referral time: 2.7 ± 3.7 months before dialysis). In the present investigation, biological and therapeutic data were the results obtained at 2.7 months before dialysis for early referred patients, and at their first nephrology consultation for intermediate–late referred patients. In the first group, we examined the therapeutic care delivered by a nephrologist (patients ‘under nephrologist care’), whereas, in the second, care referred to practices delivered before the nephrologists’ intervention (patients ‘not under nephrologist care’).

Data included age, sex, year of first dialysis (2005 or 2006), body mass index (BMI), primary renal disease and comorbid conditions. BMI was calculated as weight (kg)/square of height (m). Primary renal disease was classified into five groups: glomerulonephritis, diabetic or hypertensive nephropathy, hereditary nephropathy and others. Comorbidity was defined as the presence of clinically significant non-renal disease (e.g. cardiac, vascular, or respiratory disease, diabetes mellitus or malignancy).

Data on BP, glomerular filtration rate (GFR), 24-h urinary protein excretion (proteinuria) and use of antihypertensive therapy at 2.7 months before dialysis (early referral) or at the first nephrology consultation (intermediate-late referral) were also considered here. BP was measured by clinical nurses who used a mercury sphygmomanometer, with patients in a sitting position after a 5-min rest. Adequate BP control was defined as systolic BP < 130 and diastolic BP < 80 mmHg, as recommended in guidelines. The GFR was estimated with the simplified equation from the Modification of Diet in Renal Disease (MDRD) trial, by calibrated serum creatinine level. Adequate control was defined as proteinuria < 0.5 g/day. The BP–proteinuria control was defined as BP < 130/80 mmHg and proteinuria < 0.5 g/day.

Antihypertensive medications used were grouped into six classes: ACEIs, ARBs, diuretics, calcium channel blockers, β blockers, antiadrenergic agents and {alpha} blockers. Combination drugs were described in terms of components.

Outcomes
Primary outcomes were BP and proteinuria, analysed as continuous variables (mean systolic and diastolic BP and mean 24-h proteinuria) and as categorical variables (BP < 130/80 mmHg and 24-h proteinuria < 0.5 g/day) for early and intermediate–late referred patients.

Data analyses
All analyses were performed with SAS version 9.1 (SAS Institute, Inc., Cary, NC, USA). We compared demographic, clinical, biological and therapeutic data between early and intermediate-late referred patients.

Antihypertensive treatments, BP and proteinuria were first compared between the two groups using bivariate analysis–Pearson chi-square test and analysis of variance for qualitative and quantitative variables, respectively. Comparisons were then made, adjusted for demographic and clinical characteristics differing between the two groups, by using multivariate regression models. A P < 0.05 was considered significant.

Categorical variables were expressed as proportions and continuous variables as mean ± standard deviation.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
Demographic and clinical characteristics
The AVENIR study included 566 ambulatory patients: 291 (51.4%) were referred to a nephrologist >1 year before and 275 (48.6%) <1 year before the initiation of dialysis. These last 275 patients were followed and referred at 95.2% to a nephrologist by their family physician. Among them, 11.2% were also treated by a cardiologist. Table 1 shows the demographic and clinical characteristics of both groups of patients. As compared with intermediate–late referred patients, those early referred were younger, more often male and less likely to have malignant disease; underlying renal disease was more often glomerulonephritis, diabetic and hereditary nephropathy in this group.


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  		Table 1 Comparison of demographic and clinical characteristics between early and intermediate–late referred CKD patients

 
The GFR of early referred patients (measured at 2.7 months before dialysis) did not differ from the GFR of those with an intermediate or late referral (measured at the first nephrology consultation); their mean values were respectively 14.2 ± 10.0 and 13.7 ± 6.0 ml/min/1.73 m2.

Therapeutic characteristics
Table 2 shows therapeutic characteristics for both groups. Intermediate–late referred patients received fewer antihypertensive agents than early referred patients. In this group, 15.6% received no antihypertensive drug prescriptions as compared with 3.8% of early referred patients (P < 0.0001). All antihypertensive classes were more often prescribed for early referred patients, with diuretics the most represented class for either group. Among early referred patients, 60.5% received RAAS inhibitors (8.5% of them having an association of ACEi and ARB) as compared with 36.7% for intermediate–late referred patients (4.9% of them having an association of ACEi and ARB).


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  		Table 2 Comparison of therapeutic characteristics between early and intermediate–late referred CKD patients

 
BP and proteinuria control
Table 3 lists results for BP and proteinuria. Early referred patients had a slightly higher mean systolic and diastolic BP and BP > 130/80 mmHg, but the difference between groups was not significant. For patients under antihypertensive treatment, BP was not optimally controlled (>130/80 mmHg) for 77.5% of early referred patients and 73.9% of intermediate–late referred patients. Among the 11 and 43 patients not receiving antihypertensive therapy in the groups with an early or intermediate–late referral, 55.6% and 61.5% respectively were hypertensive as defined by BP > 130/80 mmHg in CKD patients.


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  		Table 3 Comparison of blood pressure and proteinuria between early and intermediate–late referred CKD patients

 
Whatever the care, <50% of all included patients underwent 24-h urinary protein excretion testing, with no difference in level between groups. However, significantly more early referred patients had proteinuria above 0.5 g/day than intermediate–late referred patients. For patients under RAAS inhibitor therapy, proteinuria was not optimally controlled (>0.5 g/day) for 93.3% of early referred patients and 80.9% of intermediate–late referred patients, but the difference was not significant when adjusted for potential confounders. Among the 43 and 82 patients not receiving RAAS inhibitor therapy in the groups with an early or intermediate-late referral, 88.4% and 76.8% respectively had a proteinuria reading above the target of 0.5 g/day (not significant). Moreover, for early and intermediate–late referred patients not treated with a RAAS inhibitor, 90.4% and 58.5% respectively received another type of antihypertensive medication (P < 0.0001, data not shown).

Overall, only 1.2% (3/245) and 5.5% (12/218) of early and intermediate–late referred patients, respectively, attained BP and proteinuria goals.



   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
Our data show that the current management of patients with advanced CKD is suboptimal as assessed by BP and proteinuria targets proposed in guidelines [11,12]. Indeed, hypertension and proteinuria were poorly controlled for most patients, whether early referred to a nephrologist or not.

Patients under nephrologist care (early referred) were prescribed significantly more antihypertensive medications, as compared to those not under nephrologist care (intermediate–late referred); this result is consistent with those from the Minutolo et al. study [16], in which two or more antihypertensive agents were prescribed for 66% of CKD patients under primary care and 83% of patients under tertiary care. Moreover, the proportion of patients receiving each antihypertensive class was always greater in the group under nephrologist care, especially for RAAS medications (60.5% of patients treated versus 36.7%). In the study by Bailie et al. [21], of patients with a mean GFR of 23.6 ± 9.6 ml/min/1.73 m2 managed in a nephrology clinic, 57% were using ACEIs or ARBs.

Regardless of these therapeutic differences, BP did not differ between our groups, and proteinuria control was achieved in more patients not under nephrologist care than under nephrologist care. This surprising result may be due to differences in demographic and clinical characteristics between the groups (age, gender, primary renal disease). However, hypertension and proteinuria results remained the same after adjustment for these characteristics. Another explanation could be related to severity of symptoms. Young patients with severe hypertension (not easily controlled by medications) and thus high risk of proteinuria [27] are more likely to be referred to a nephrologist by the family physician. Thus, patients referred to a nephrologist, whose disease is more complicated than those under primary care, require more intensive treatment.

Whatever the type of care, our results reveal that BP and proteinuria management is not completely satisfactory. We found BP control achieved in only one-quarter of all patients under antihypertensive therapy. This is quite consistent with previous results showing a BP control rate between 12% [20] and 37% [18]. Now, efforts are needed to understand the reasons for these bad results. They could be related to the antihypertensive therapy, not as aggressive as it should be; indeed, it is recognized that target BP values for CKD patients are difficult to achieve and require generally three or four antihypertensive medications [9,11]. Nevertheless, in our sample, the mean number of antihypertensive drugs for all patients was 2.7 ± 1.6 and 3.1 ± 1.5 for patients under nephrologists’ care, indicating that physicians, and especially nephrologists, were doing their very best to control BP. Failure to achieve BP goals could be then related to patients not enough adherent to their medications or their dietary prescription. Nonadherence to medications is well known worldwide, especially for oral medications that need to be taken long term, such as antihypertensive agents [28]. The sodium restriction to no more than 6 g/day is also known to be difficult to achieve. However, this restriction becomes even more critical for CKD patients because of the marked salt sensitivity of BP, and maximizing the effectiveness of medications is essential [29]. Interventions such as patient education may improve adherence to drug and dietary prescriptions [30].

Proteinuria control was achieved in only 1 of 10 of our patients under RAAS inhibitor therapy. This result could be related to the dosage of RAAS inhibitors prescribed. The efficacy of RAAS inhibitors in reducing proteinuria may be limited by currently recommended doses, which are based on BP-lowering effects. Data from clinical trials are now showing the benefit of ‘supratherapeutic’ doses to improve their ability to decrease proteinuria [31,32]. Never- theless, we are not allowed to conclude about dosage because this information was not collected here. Moreover, we found a low rate of combination therapy with ACEIs and ARBs (5.1% of all patients), despite the evidence of its additive antiproteinuric effect of up to 40% [33]. Also, national guidelines [12] recommend this combination when proteinuria remains >0.5 g/day under monotherapy. In our study, the physicians may have been reluctant to use ACEI–ARB combinations or ‘supratherapeutic’ doses of RAAS inhibitors because of concerns about hyperkalaemia or haemodynamic-mediated increase in serum creatinine, which are frequent in the few weeks before dialysis.

Among the 125 patients not receiving an RAAS inhibitor who underwent measurement for proteinuria, 80% showed proteinuria > 0.5 g/day and should have received this treatment. Actually, RAAS inhibitors did not appear to be prescribed in preference to other antihypertensive medications such as diuretics; diuretics are helpful for most CKD patients in reducing extracellular fluid volume expansion but guidelines recommend them as second-line therapy, after initial dosing with an ACEI or ARB [12]. Diuretics may have been preferred because of high level of kalaemia or their visible effects on symptoms, such as oedema.

The first limitation of our study is strictly dependant on the observational design. A bias of indication may have led to BP and proteinuria control not better for patients under nephrologist care, despite a greater use of antihypertensive and RAAS therapy. This likely bias does not allow us to conclude about the participation of hypertension and proteinuria control in the decreased morbi-mortality of CKD patients referred early to a nephrologist. Another limitation is the lack of urinary protein excretion result in half of the patients. However, patients in whom proteinuria was quantified were most probably those showing a urinary dipstick analysis positive. So, our results about proteinuria control are probably underestimated. A last limitation that may be objected concerned BP measurements, gathered in the course of clinical care and not performed under standardized conditions. However, they represent the data that clinicians were using to make decisions.

In conclusion, our study provides comprehensive information about therapeutic care and hypertension and proteinuria control in patients with advanced CKD. A few studies have already examined BP control for this population [16–21], but none have analysed proteinuria results. However, hypertension and high proteinuria level are often associated, and it may appear to be not consistent to analyse them separately. Our study confirms the poor level of BP control in CKD patients [16–21], and adds to current knowledge that proteinuria is also poorly controlled. These results suggest that guidelines are probably too strict for clinical practice, particularly at an advanced stage where the recommended targets are the same as at earlier stages. They also support the need for educational interventions to improve patient adherence to prescriptions and to expand on the use of RAAS inhibitors. Likewise, the development of guidelines on the optimal doses of RAAS inhibitors to reduce proteinuria is expected.



   Acknowledgments
 
The authors wish to thank the patients, nephrologists and medical directors of the participating hospitals in Lorraine. The AVENIR study was supported by a grant from the Hospital Program of Clinical Research (PHRC 2004) of the French Ministry of Health.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 16. 7.08
Accepted in revised form: 17. 9.08


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