effectiveness of antihypertensive treatment in patients with chronic kidney disease

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Page 1: Effectiveness of Antihypertensive Treatment in Patients With Chronic Kidney Disease

Effectiveness of Antihypertensive Treatment inPatients With Chronic Kidney DiseaseEwa Krol, MD,* Piotr Czarniak, MD,† and Bolesław Rutkowski, MD*

Objective: Hypertension is closely associated with chronic kidney disease (CKD) and is one of the main factors of

progression of CKD. Early detection of CKD allows introducing a therapy that slows the progression of CKD.

Setting: A prevalence of hypertension and effectiveness of its treatment were assessed during the accomplish-

ment of the Program for Early Detection of CKD in Poland (PolNef).

Results: In 456 of a total of 2476 participants of PolNef program (269 females, 187 males), CKD was recognized.

Diagnosis of CKD was made according to classification proposed by K/DOQI and KDIGO. Estimated glomerular fil-

tration rate (eGFR) from serum creatinine, albuminuria and ultrasound examination were the main diagnostic tools.

Hypertension was defined on the basis of actual antihypertensive treatment or on the basis of medium value ($140

and/or $90) of three separate measurements of blood pressure. Frequency of hypertension and effectiveness of its

treatment, frequency of overweight and obesity, microalbuminuria, and abnormalities in ultrasound examination of

urinary system were studied.

Conclusion: Of the CKD population, 68% were hypertensive, 21% remained without antihypertensive medication,

and 22% on medication were effectively treated. Kidney insufficiency with eGFR below 60 ml/min/1.73 m2 was rec-

ognized in 9% of CKD population. Also, 63% of women and 39% of men without hypertension had normal body mass

compared to 19% of people with CKD and hypertension. Microalbuminuria was found in 51% of women and 66% of

men with CKD and hypertension. Increased echogenicity of kidney and simple cysts were detected significantly

more often in hypertensive patients.

� 2008 by the National Kidney Foundation, Inc.

PREVALENCE OF HYPERTENSION inCKD population is high, ineffectively treated,

mostly using one hypotensive drug. Frequency ofmicroalbuminuria in CKD patients with hyper-tension exceeds 50%. Screening tests for detectionof CKD seems to be necessary among overweightand obese subjects, especially while accompaniedby hypertension. An ultrasound diagnostic ofurinary tract should be performed in hypertensivepeople.

Hypertension is both a well-established causeand a common complication of chronic kidneydisease (CKD).1,2 Hypertension increases the

*Department of Nephrology, Transplantology and Internal Dis-

eases, Medical University of Gdansk, Poland.

†Department of Pediatric Nephrology and Hypertension, Medical

University of Gdansk, Poland.

Address reprint requests to Ewa Krol, MD, PhD, Department of

Nephrology, Transplantology and Internal Diseases, Medical Univer-

sity of Gdansk, Debinki 7, 80-211 Gdansk, Poland. E-mail:[email protected]

� 2008 by the National Kidney Foundation, Inc.

1051-2276/08/1801-0026$34.00/0

doi:10.1053/j.jrn.2007.10.027

134 Jo

risk of loss of renal function and is one of themain factors of progression of renal insufficiency.Aggressive blood pressure control is the mostimportant intervention to slow the rate of declinein glomerular filtration rate (GFR) in patientswith CKD. Target blood pressure recommendedby National Kidney Foundation K/DOQI clini-cal practice guidelines for CKD patients hasbeen set at less than 130/80 mm Hg.3 The benefitof aggressive control of blood pressure is mostpronounced in patients with albuminuria. Kidneydisease is often progressive once GFR decline by25% of normal. For that reason early detectionof CKD is very important to prevent further de-cline in kidney function. Identification of kidneydamage in earliest stages allows the introductionof therapy that may slow the progression of renaldisease. On the other hand, early detection andeffective treatment of hypertension is essentialstrategy to prevent initiation of kidney damageand further progressive loss of renal function aswell.

A prevalence of hypertension in people withnewly diagnosed CKD and efficiency of its treat-ment were assessed during the accomplishment of

urnal of Renal Nutrition, Vol 18, No 1 (January), 2008: pp 134–139

Page 2: Effectiveness of Antihypertensive Treatment in Patients With Chronic Kidney Disease

ANTIHYPERTENSIVE TREATMENT IN CKD 135

the Program for Early Detection of CKD inPoland (PolNef).4,5

Methods

Starogard Gdanski, a 60,000-population citydistrict in North Poland, was randomly chosenfrom the two districts with population between50,000 and 100,000 in Pomeranian administrativeregions. The address list of all adult inhabitantswas obtained from the local administration withthe permission of the mayor of Starogard Gdanski.It was estimated that approximately 10,000 invita-tions to adult inhabitants of chosen district shouldbe send taking into consideration 25% to 30% re-sponding rate and assuming similar percentage ofmicroalbuminuria around 7% in the Polish popu-lation compared to the Dutch one (PREVEND).Finally, from the population of 9700 adult inhab-itants randomly chosen from the address list,a group of 2501 responded, brought a morningurine sample, allowed for blood pressure measure-ment, and filled in a questionnaire on demographiccharacteristics, weight and height, symptoms ofkidney diseases, medications, and coexistence ofother diseases especially hypertension, diabetes,and cardiovascular diseases. Every participantwas assessed for CKD according to the algorithmconstructed specially for early detection of kidneydamage.3 A dipstick test for microalbuminuria(Micral-Test II, Roche Diagnostics Ltd, GB)was performed to detect albumin in first morningurine sample. The cut-off point for this test is al-bumin concentration in urine equal to 20 mg/L.Moreover, albumin concentration in urine wasmeasured from separate urine sample brought byparticipant before renal consultation (MultigentMicroalbumin assay on the Architect ci 8200 sys-tem, Abbott Laboratories, Inc.). Any amount ofalbumin can be detected using turbidimetricmethod. Positive dipstick test for microalbuminu-ria and concentration of albumin measured inurine equal or more than 20 mg/L using bothmethods was assumed as albuminuria. Serum cre-atinine was measured using the modified methodof Jaffe’s reaction in an automated Architect ci8200 analyzer. The abbreviated, four-parameterMDRD formula was used to estimate GFR(eGFR) in all individuals qualified for renal con-sultation. When calculating the eGFR, serumcreatinine values as mg/dl to two decimal placeswere used. We assumed that a participant had

diabetes mellitus if he was on hypoglycemic med-ication or his primary care physician answeredpositively questions concerning this disease. Diag-nosis of hypertension was made on the basis ofactual antihypertension treatment or on the basisof medium value of blood pressure ($140 and/or $90 mm Hg) of three separate measurementsusing a mercury sphygmomanometer with anadequate cuff, after no less than 5-minute rest ina sitting position. Blood pressure measurementswere taken at least tree times on separate occa-sions: during first visit in outpatient health centertogether with dipstick test for albuminuria detec-tion and questionnaire, than during the visit inprimary care physician who selected people forfurther renal consultation according to algorithm,and finally during renal consultation. If arterialblood pressure exceeded values of 140 for systolicand/or 90 mm Hg for diastolic during the visitin the office of a primary care physician, fewadditional home blood pressure measurementswere recommended.6 In a case of normal valuesof home measured blood pressure, the valueobtained in primary care physician was ignoredto minimize emotional increases of bloodpressure.

Ultrasound examinations were performed inthe ultrasound diagnostic nephrologist withphased-array transducer 2-5 MHz (B&K 2002Panther). The length of kidneys, renal parenchy-mal thickness and echogenicity were assessed onlateral decubitus position, after 8 hours fasting.Liver echogenicity, and when liver parenchymawas hyperechoic, spleen echogenicity were usedas a standard reference. Participant was enrolledinto the study if, in responding to the invitation,brought a morning sample of urine for microal-buminuria test, filled the questionnaire, had bloodpressure measurements, laboratory and ultrasoundexaminations if needed, according to the given al-gorithm. Fever, seizures, pain during urination,and excessive physical activity like exercises forat least 45 minutes on the day before urine testfor microalbuminuria were temporary exclusioncriteria. The participants were invited again afterresolution of those symptoms. Body mass index(BMI) was calculated as the ratio of weight inkilograms to height in meters squared. The defi-nition of obesity was made on the basis of BMI:BMI below 25 kg/m2 was considered as a normalweight, $25 and ,30 as overweight, and $30kg/m2 as obesity.

Page 3: Effectiveness of Antihypertensive Treatment in Patients With Chronic Kidney Disease

KROL ET AL136

Results

In 456 subjects from the total number of 2475participants, who fulfilled inclusion criteria, adiagnosis on CKD was established. Characteris-tics of the CKD group according to the genderwere given in Table 1. 68% of CKD populationwas hypertensive, and 18.6% had diabetes. Kid-ney insufficiency with eGFR below 60 ml/min/1.73 m2 was recognized in 9% of CKDgroup. 63% of women and 39% of men withouthypertension had normal body mass compared toonly 19% of people with CKD and hypertension(Figure 1). One fifth (20.6%) of hypertensiveparticipants with recognized CKD were withoutany hypotensive treatment. Majority out of 247treated hypertensive participants with CKD(51%) were on monotherapy, 33% on two anti-hypertensive agents, 14% on three medications,and only 1.6% and 0.4% on four or five drugs,respectively.

The percentage of participants with CKD andelevated blood pressure (above 140 for systolicand/or 90 for diastolic) is given in Figure 2.

Assuming that effective antihypertension treat-

ment resulted in systolic blood pressure below

140, and diastolic below 90 mm Hg, 22% of par-

ticipants with CKD and hypertension achieved it,

16% had elevated systolic, and 6% had elevated di-

astolic blood pressure. The normal blood pressure

120/80 and below was achieved in 12% of the

subjects with CKD and treated hypertension.

The percentage of patients effectively treated ac-

cording to the number of drugs used was 24%,

20%, and 24% for one, two, or three drugs, re-

spectively. No one on four- or five-drug therapy

was efficiently treated. The proportion of women

effectively treated increased from 21% (one drug)

to 29% (two drugs) or 27% (three drugs) com-

pared to decreased fraction of adequately treated

men: 30% (one drug), 9% (two drugs), and 17%

(three drugs). Effectiveness of antihypertensive

treatment according to the stage of CKD was

given on Figure 3. Albuminuria was found in

51% of women and 66% of men with CKD and

hypertension. Increased echogenicity of kidney

Table 1. Characteristics of Female and Male Participants with CKD

Sex [n (% of participants with CKD)] Female 269 (59%) Male 187 (41%)

Age (years)

Range 18 O 80 18 O 83

Mean 6 SD 54.1 6 14 56.6 6 13

Mediana (25%, 75%) 56 (48, 65) 58 (50, 66)BMI (kg/m2)

Range 15.9 O 49.5 18.2 O 46.8

Mean 6 SD 27.7 6 5.9 28.4 6 4.9

Mediana (25%, 75%) 27.3 (23.6, 31.2) 27.8 (25, 31.6)Systolic blood pressure (mm Hg)

Range 80 O 220 90 O 250

Mean 6 SD 139 6 24.1 142 6 23.8

Mediana (25%, 75%) 140 (120, 155) 140 (125, 160)Diastolic blood pressure (mm Hg)

Range 55 O 120 40 O 120

Mean 6 SD 85.8 6 12.1 87.5 6 12.8Mediana (25%, 75%) 85 (80, 92) 90 (80, 95)

Hypertension [n (% of women and men with CKD)] 179 (66.5%) 132 (70.6%)

Smoking [n (% of women and men with CKD)] 50 (18.6%) 59 (31.6%)

Diabetes [n (% of women and men with CKD)] 32 (11.9%) 35 (18.7%)Race [n (% of women and men with CKD)]

Caucasian white 269 (100%) 187 (100%)

Number of patients in CKD stages

[n (% of women and men with CKD)]1 eGFR . 90 63 (23.4%) 70 (37.4%)

2 eGFR: 60 O 89.9 180 (66.9%) 101 (54%)

3 eGFR: 30 O 59.9 25 (9.3%) 15 (8%)4 eGFR: 15 O 29.9 1 (0.4%) 1 (0.5%)

5 eGFR , 15 0 0

CKD, chronic kidney disease; BMI, body mass index; eGFR, estimated glomerular filtration rate by MDRD formula.

Page 4: Effectiveness of Antihypertensive Treatment in Patients With Chronic Kidney Disease

ANTIHYPERTENSIVE TREATMENT IN CKD 137

and simple cysts were detected significantly moreoften in hypertensive subjects.

Discussion

The prevalence of hypertension in people withnewly recognized CKD is high and oscillates be-tween 67% in women and 71% in men. There is

0%

10%

20%

30%

40%

50%

60%

70%

< 25 25 < 30

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

BMI [kg/m2]

≥ 30

< 25 25 < 30 ≥ 30

B

A

without HAwith HA

without HAwith HA

Figure 1. Frequency of normal body weight, over-weight, and obesity according to body mass index(BMI) in women (A) and men (B) with chronic kidneydisease in groups without and with hypertension(HA).

0%

20%

40%

60%

80%

100%

120%

> 90 89.9 ÷ 60 59.9 ÷ 30 29.9 ÷ 15

mL/min/1.73 m2

totalwomenmen

Figure 2. Percentage of chronic kidney diseaseparticipants with blood pressure equal or above140/90 mm Hg.

nothing unexpected while arterial hypertensionis closely related to renal diseases as its commonconsequence or at the same time as its cause. Itis worthy to mention that influence of whitecoat hypertension, even it is highly prevalent inCKD as was published recently by Minutoloet al.,7 was minimized in our study by home bloodpressure measurements recommended for partici-pants with high blood pressure during the firstvisit in a doctor’s office. In general, Polish popu-lation arterial hypertension occurs in 30% of adultinhabitants based upon the epidemiological studyNatpol III (2002),8 and 33% according to theWOBASZ study (2004).9 The prevalence of arte-rial hypertension in Poland is similar to the prev-alence in United States (28%), Africa (28%), orAustralia (29%) and lower compared to other Eu-ropean countries such as Germany (55%), UnitedKingdom (42%), and Spain (47%).10–13 The effec-tiveness of antihypertensive treatment is surpris-ingly low: from 3% in Africa, 5% in Spain, 8%in Germany, 10% in United Kingdom, to 13%in Australia and 31% in the United States. Theefficiency of this treatment in general Polishpopulation is around 12%. Compared to generalpopulation, the 22% of effectiveness of manage-ment of hypertension in the group of peoplenewly diagnosed by CKD seems to be ratherhigh. However, keeping in mind that hyperten-sion is one of the most important factors promot-ing loss of renal function and progression ofkidney disease, hypertension in CKD patientsshould be treated much more aggressively. Effi-cacy of monotherapy was about 24%. Treatmentwith two or more antihypertensive agents wasno more efficient: 20% of CKD patients on two

0%

5%

10%

15%

20%

25%

30%

> 90 89.9 ÷ 60 59.9 ÷ 30 29.9 ÷ 15

mL/min/1.73 m2

totalwomenmen

Figure 3. Effectiveness of treatment of hypertensivepatients in different stages of chronic kidney dis-ease.

Page 5: Effectiveness of Antihypertensive Treatment in Patients With Chronic Kidney Disease

KROL ET AL138

drugs and 24% on three reached blood pressurebelow 140 mm Hg for systolic and less than 90for diastolic. The efficiency of treatment of hyper-tension was generally better for female. Onlymonotherapy was more efficient for male (30%versus 21%) probably due to a better compliancewith smaller amount of drug. In a small group ofpatients on four and five medications (a total ofonly five persons) nobody reached these levelsof blood pressure. Moreover, there is other strik-ing information which should worry any ne-phrologist: the more advanced stage of kidneydisease with larger decline in renal function, theless efficient therapy of hypertension. Inhibitorsof angiotensin-converting enzyme (ACE) wereused in 61% of all hypertensive patients withCKD; they were used in the first two stages ofCKD to only 19% and 30%, respectively. It seemsworthy to mention that none of the CKD patientswas taking angiotensin II receptor (AT II)blockers. So none of the patients was on doubleblockade of renin-angiotensin system. One ofthe reasons could be the high cost of AT IIblockers, but on the other hand the combineduse of ACE and AT II blockers. So none of thepatients were on double blockade of renin-angiotensin system. One of the reasons could bethe high cost of AT II blockers in Poland. Also,the combined use of ACE inhibitor and AT IIblockers seems to be not popular by doctors ofother specialty. This fact has shown clearly thateducation efforts in this matter are necessary.One has to remember that this type of combina-tion is more often recommended as nephropro-tective regimen.14 Also our own studies haveshown that double blockade of renin-angiotensinsystem is more effective than ACE or AT IIblockers used as monotherapy.15

Albuminuria caused by glomerular capillaryinjury is proposed to be a marker for diffuse endo-thelial dysfunction and independent risk factor forcardiovascular disease.16 A majority of examinedhypertensive subjects with CKD had albuminuria.Only albumin level more than 20 mg/L was takeninto account during screening for albuminuria inPolNef study. On the other hand, the risk forcardiovascular events increases at every level ofurinary albumin excretion, even at levels withinthe normal ranges. It means the problem of albu-minuria in hypertensive patients with CKD couldbe even larger. With increasing epidemic ofobesity and type II diabetes all over the world

the prevalence of albuminuria will expand in thefuture. The practical clinical conclusion flowsfrom this lesson is a wider use of nephroprotectiveagents as ACE inhibitors.

There is not only very well known evidence ofa relationship between obesity and the future devel-opment of type II diabetes and cardiovascular dis-eases, but also data of an important correlationbetween obesity and albuminuria or CKD aswell.17–19 Thus, as it was proposed by Tomaszewskiet al.,20 early treatment of hypertension, especiallyof young obese individuals, may prevent theprogression of renal hyperfiltration to CKD. More-over, those data suggest the need for implementa-tion of weight loss strategies at least in peoplewith others risk factors for development of CKD.

Ultrasound examinations showed a higherprevalence of hypertension in participants withsimple renal cyst. Therefore, further studies areneeded to establish whether subjects with renalcysts are at greater risk to develop hypertension,and as a consequence CKD.

Our study has shown that like in other coun-tries and communities also in Poland, CKD isconnected with high prevalence of hypertension.However, elucidation of cause-effect issues be-tween these two important syndromes needsfurther analysis of our studied population. Theeffectiveness of treatment of hypertensive patientswith CKD should be absolutely improved, espe-cially in early stages, what in consequence couldslow further progression of kidney damage.

References

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