Calcium Channel Blockers and Renal Protection:

Insights from the Latest Clinical Trials

Julian Segura, Jose A. Garca-Donaire, and Luis M. Ruilope
Hypertension Unit, Hospital 12 de Octubre, Madrid, Spain
Calcium channel blockers have been widely used in clinical practice because of their antihypertensive capacity. Prevention of
renal damage is a very important aim of antihypertensive therapy. This is particularly so taking into account the high
prevalence of chronic kidney disease (CKD) in the general population. Recent data have shown that CKD is related to the
absence of adequate BP control and also to the clustering of other cardiovascular risk factors seen in the metabolic syndrome.
The knowledge of the capacities of the different antihypertensive drugs or their combinations to simultaneously control BP
while protecting the kidney and avoiding the facilitation of metabolic alterations is warranted. Recent data from the
Intervention as a Goal in Hypertension Treatment trial, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack
Trial, and African American Study of Kidney Disease and Hypertension (AASK) allow the conclusion that in hypertensive patients
with preserved renal function or with CKD, calcium channel blockers are effective antihypertensive drugs to be considered alone
or in combination with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker.
J Am Soc Nephrol 16: S64 S66, 2005. doi: 10.1681/ASN.2004110969

alcium channel blockers (CCB) are widely used for the

treatment of cardiovascular disease, particularly angina pectoris, arrhythmias, and arterial hypertension.
Their beneficial effects are related to systemic vasodilation
caused by the inhibition of the inward flow of calcium ions
through the L-type calcium channels in the cell membrane.
Three main classes of CCB are in current use: The benzothiazepines (diltiazem), phenylalkylamines (verapamil), and dihydropiridines (nifedipine, amlodipine, and others).
A growing interest in the investigation of renal function in
big trials that deal with different aspects of cardiovascular
disease has developed in recent years. This is justified by different reasons, including the high prevalence of nephrosclerosis
as a cause of ESRD (1) and the capacity of minor alterations of
renal function to predict a poor outcome for the patients (2).
The finding of a small increase in serum creatinine values, a
diminished estimated GFR (60 ml/min per 1.73 m2), microalbuminuria, and/or proteinuria heralds a significant elevation in cardiovascular events and death as well as in total
mortality (2,3). These alterations are frequent in the hypertensive population and are related to an inadequate BP control and
also to the clustering of other associated risk factors, particularly those seen in the metabolic syndrome (2 4).
The elevated prevalence of albuminuria and/or a diminished
renal function in the general population in United States (5) and
the frequent association of these alterations with high BP reinforces the need to know more about the long-term renal effects
of the different antihypertensive agents or their combinations
in the hypertensive population, in particular in patients who
present with high BP and metabolic syndrome. This necessity is

Address correspondence to: Dr. Luis M Ruilope, Hypertension Unit, Hospital 12

de Octubre, Avenue Cordoba s/n, 28041 Madrid, Spain. Phone: 34-91-3908198;
Fax: 34-91-3908035; E-mail: ruilope@ad-hocbox.com
Copyright 2005 by the American Society of Nephrology

related to the potential capacity of these drugs to worsen the

metabolic profile of the hypertensive patient, leading to an
increase in the development of diabetes during the chronic
administration of certain antihypertensive agents, thus facilitating further renal damage and cardiovascular risk (6).

CCB and Renal Protection in Recent Trials

in Hypertensive Patients
Two recently published trials in which different antihypertensive agents were compared have shown that CCB could be
particularly positive for the long-term maintenance of GFR
levels when compared with a diuretic and with an angiotensinconverting enzyme (ACE) inhibitor. These were the Intervention as a Goal in Hypertension Treatment trial (INSIGHT) and
the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (7,8).
The INSIGHT study randomized 6321 hypertensive patients
who had one or more associated risk factors to the dihydropyridine CCB, nifedipine gastrointestinal therapeutic system
(GITS), or the diuretic combination hydrochlorothiazide/
amilozide for the treatment of hypertension. BP control
throughout the study was similar in both groups, with no
statistically significant difference in the primary combined end
point of cardiovascular death, nonfatal myocardial infarction,
stroke, or heart failure. However, there was a small but significant decrease in estimated creatinine clearance during follow-up in the diuretic-treated patients compared with the one
observed in those who received nifedipine GITS (7), suggesting
that antihypertensive treatment that is based on a long-acting
dihydropyridine may offer better renoprotection than therapy
that is based on the diuretic combination co-amilozide.
The recent publication of the main results of the ALLHAT
study also included the analysis of the changes observed in
serum creatinine, slope of the reciprocal of serum creatinine,
ISSN: 1046-6673/1603-0064

J Am Soc Nephrol 16: S64 S66, 2005

and also estimated creatinine clearance (8). The results show

that a 448 of 33,357 patients developed ESRD without significant differences among the three arms of the study. The slopes
of the reciprocal of serum creatinine over time were virtually
identical in the chlorthalidone and lisinopril groups, whereas
the decline in the amlodipine slope was significantly less than
that of the chlorthalidone arm. Finally, the estimated creatinine
clearance exhibited a significantly better preservation in the
amlodipine arm that had a final mean value of 75.1 ml/min,
than compared with 70.0 and 70.7 ml/min in the chlorthalidone
and lisinopril groups, respectively.
These results seem to differ from the available evidence
indicating that the administration of an ACE inhibitor or an
angiotensin receptor blocker (ARB) is required to protect renal
function beyond the benefit obtained by BP control (9). The
better evolution observed in both the slope of the reciprocal of
serum creatinine and the estimated creatinine clearance with a
CCB argues against recently published comparative studies in
which an ACE inhibitor or an ARB were shown to be better
than a CCB in primary renal disease, in type 2 diabetic nephropathy, and in black patients with nephrosclerosis (10 12).

CCB, BP Control, and Renal Protection in

the Presence of Preserved Renal Function
The capacity of a CCB to protect the kidney in hypertensive
patients seems to depend mainly on the capacity of these drugs
to lower BP as shown by the analysis of renal data in the
Systolic Hypertension in Europe study (13), which demonstrated that lowering BP with nitrendipine caused a significant
reduction in proteinuria and renal insufficiency events in patients who were actively treated with nitrendipine compared
with those who took placebo (13).
The maintenance of a strict BP control represents the most
relevant means to maintain a preserved renal function in hypertensive patients. In fact, a recent publication indicated that a
very strict BP control attained a similar degree of renal protection in patients with type 2 diabetes, matching the control
attained with enalapril or with the CCB nisoldipine (14). A
good control of systemic BP counteracts the risk for afferent
arteriolar vasodilation induced by the CCB by impeding the
transmission of a still elevated systemic BP (15). A CCB then
can be renoprotective in the presence of a preserved GFR
provided that micro- or macroalbuminuria is not present. If
albumin excretion is elevated, then an ACE inhibitor or an ARB
is required to obtain full protection of the kidney (16,17).
The ALLHAT study demonstrated a very good control of BP
with final mean values for systolic/diastolic BP of 133.9/75.4,
134.7/74.6, and 135.9/75.4 mmHg for chlorthalidone, amlodipine, and lisinopril, respectively, and with 66% of patients
achieving BP values 140/90 mmHg (8). Small but significant
differences in the control of systolic BP were seen in favor of the
chlorthalidone arm, which further favor the concept of a protective effect of amlodipine. It will be interesting to see how
many cases of crossover to an ACE inhibitor performed in
patients who received the diuretic or the CCB were due to the
presence of a diminished renal function and whether this could
have contributed to create some biases in the final results.

CCB and the Kidney in Essential Hypertension

S65

However, follow-ups longer than 5 yr are required to prove

which is the most adequate antihypertensive therapy to maintain a preserved renal function.

CCB, BP Control, and Nephroprotection in

Patients with Established Chronic Kidney
Disease
According to recently published guidelines (16,17), the two
main strategies to prevent progression of renal damage and to
reduce cardiovascular risk in hypertensive patients with
chronic kidney disease (CKD) are a strict BP control and the
inhibition of the renin-angiotensin system. A strict BP control
can be accompanied by reduction of proteinuria, but usually
the fall in mean BP required to see a significant fall in proteinuria with practically any antihypertensive medication is 20
mmHg (18). However, recent data from the African American
Study of Kidney Disease and Hypertension (AASK) study have
shown that, in black patients, attained mean BP values of
128/78 mmHg did not differ from 141/85 mmHg in affording
additional benefit of slowing the progressive fall in GFR values
in hypertensive nephrosclerosis (12). This study suggests that
in patients with nondiabetic renal disease, blockade of the
renin-angiotensin system with either ACE inhibitor or ARB is
superior to CCB in the progression of nephropathy in proteinuric patients. Amlodipine did seem to be equally effective as
the ACE inhibitor when proteinuria was absent (12).
Data in proteinuric patients with type 2 diabetes obtained in
the Irbesartan Diabetic Nephropathy Trial study (11) also
showed that at equal BP levels, patients who received irbesartan showed a 20% risk reduction when compared with those
who received placebo and a 23% risk reduction when compared
with those who were treated with amlodipine. There was no
difference between the amlodipine and placebo groups (11).
The Reduction of Endpoints in Noninsulin dependent diabetes
mellitus with the Angiotensin II Antagonist Losartan trial included a patient population similar to that investigated in
Irbesartan Diabetic Nephropathy Trial, who were randomized
to receive losartan or placebo. It is interesting that 80% of
patients in both groups were treated adjunctively with CCB to
achieve the goal of BP control (19). The positive effect of the
ARB to halt the progression of renal failure was not jeopardized
by the simultaneous administration of a CCB. Furthermore, the
antiproteinuric effect of losartan was not abrogated by the
presence of a CCB. Nondihydropiridine CCB have been shown
to lead to a reduction in albuminuria or proteinuria, in particular when associated to an ACE inhibitor (20,21).
The data of the AASK (12) point to a positive effect on renal
function of amlodipine in patients with nephrosclerosis without proteinuria. Such an effect must be attributed to the existence of a good BP control. However, here again, longer followups are required to prove the capacities of an ACE inhibitor or
an ARB to obtain more complete renal protection in these
patients (22).

Conclusions
In hypertensive patients with or without CKD, CCB are
excellent antihypertensive drugs. The presence of microalbu-

S66

Journal of the American Society of Nephrology

minuria or proteinuria forces the need to use an ACE inhibitor

or an ARB but does not impede the consideration of a CCB as
a part of the combination of agents that will be required by
most, if not all, patients. In the absence of albuminuria and with
a preserved GFR (60 ml/min), a CCB can be contemplated as
first-step therapy and seems to preserve GFR in an adequate
manner. In the presence of a diminished GFR without albuminuria, a CCB can be used as first-step therapy. However, a high
percentage of patients will require combination therapy, and
the addition of an ACE inhibitor or an ARB will be adequate.

J Am Soc Nephrol 16: S64 S66, 2005

11.

12.

References
1. National Institute of Diabetes and Digestive and Kidney Diseases: US Renal Data System: Annual Data Report. Bethesda,
MD, National Institutes of Health, National Institutes of Diabetes and Digestive and Kidney Disease, 1989
2. Ruilope LM, van Veldhuisen DJ, Ritz E, Luscher TF: Renal
function: The Cinderella of cardiovascular risk profile.
J Am Coll Cardiol 38: 17821787, 2001
3. Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton
B, Hamm LL, McCullough PA, Kasiske BL, Kelepouris E,
Klag MJ, Parfrey P, Pfeffer M, Raij L, Spinosa DJ, Wilson
PW; American Heart Association Councils on Kidney in
Cardiovascular Disease, High Blood Pressure Research,
Clinical Cardiology, and Epidemiology and Prevention: Kidney disease as a risk factor for development of cardiovascular
disease: A statement from the American Heart Association
Councils on Kidney in Cardiovascular Disease, High Blood
Pressure Research, Clinical Cardiology, and Epidemiology
and Prevention. Circulation 108: 2154 2169, 2003
4. Chen J, Muntner P, Hamm LL, Jones DW, Batuman V,
Fonseca V, Whelton PK, He J: The metabolic syndrome and
chronic kidney disease in US adults. Ann Intern Med 140:
167174, 2004
5. Eknoyan G, Hostetter T, Bakris GL, Hebert L, Levey AS,
Parving HH, Steffes MW, Toto R: Proteinuria and other
markers of chronic kidney disease: A position statement of
the National Kidney Foundation (NKF) and the National
Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK). Am J Kidney Dis 42: 617 622, 2003
6. Padwal R, Laupacis A: Antihypertensive therapy and incidence of type 2 diabetes. Diabetes Care 27: 247255, 2004
7. Brown MJ, Palmer CR, Castaigne A, de Leeuw PW, Mancia
G, Rosenthal T, Ruilope LM: Morbidity and mortality in
patients randomised to double-blind treatment with a longacting calcium-channel blocker or diuretic in the International
Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 356: 366 372, 2000
8. The ALLHAT Officers and Coordinators for the ALLHAT
Collaborative Research Group: Major outcomes in highrisk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker versus diuretic. The Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA
288: 29812997, 2002
9. Remuzzi G, Ruggenenti P, Perico N: Chronic renal disease:
Renoprotective benefits of renin-angiotensin system inhibition. Ann Intern Med 136: 604 615, 2002
10. Marin R, Ruilope LM, Aljama P, Aranda P, Segura J, Diez
J: A random comparison of fosinopril and nifedipine GITS

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

in patients with primary renal disease. J Hypertens 19:

18711876, 2001
Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA,
Lewis JB, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I;
Collaborative Study Group: Renoprotective effect of the
angiotensin-receptor antagonist irbesartan in patients with
nephropathy due to type 2 diabetes. N Engl J Med 345:
851 860, 2001
Wright JT, Bakris G, Greene T, Agodoa LY, Appel LJ,
Charleston J, Cheek D, Douglas-Baltimore JG, Gassman J,
Glassock R, Hebert L, Jamerson K, Lewis J, Phillips RA,
Toto RD, Middleton JP, Rostand SG; African American
Study of Kidney Disease and Hypertension Study Group:
Effect of blood pressure lowering and antihypertensive
drug class on progression of hypertensive kidney disease.
Results from the AASK trial. JAMA 288: 24212431, 2002
Voyaki SM, Staessen JA, Thijs L, Wang JG, Efstratopoulos
AD, Birkenhager WH, de Leeuw PW, Leonetti G, Nachev C,
Rodicio JL, Tuomilehto J, Fagard R; Systolic Hypertension in
Europe (Syst-Eur) Trial Investigators: Follow-up of renal
function in treated and untreated older patients with isolated
systolic hypertension. Systolic Hypertension in Europe (SystEur) Trial Investigators. J Hypertens 19: 511519, 2001
Schier RW, Estacio R, Esler A, Mehler P: Effects of aggressive blood pressure control in normotensive type 2 diabetic
patients on albuminuria retinopathy and strokes. Kidney
Int 61: 1086 1097, 2002
Romero JC, Ruilope LM, Bontley MD, Fiksen-Olsen MJ,
Lahera V, Vidal MG: Comparison of the effects of calcium
antagonist and converting enzyme inhibitor on renal function under normal and hypertensive conditions. Am J Cardiol 62: 59G 68G, 1988
Chobanian A, Bakris GL, Black HR, Cushman W, Green
LA, Izzo JL, Jones DW, Materson BJ, Oparil S, Wright JT,
Roccella E: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The JNC 7 Report. JAMA
289: 2560 2572, 2003
Guidelines Committee: 2003 European Society of Hypertension-European Society of Cardiology guidelines for the
management of arterial hypertension. J Hypertens 21: 1011
1053, 2003
Peterson JC, Adler S, Burkart JM, Greene T, Hebert LA,
Hunsicker LG, King AJ, Klahr S, Massry SG, Seifter JL:
Blood pressure control, proteinuria, and the progression of
renal disease. The Modification of Diet in Renal Disease
Study. Ann Intern Med 123: 754 762, 1995
Brenner BM, Cooper MD, de Zeeuw D, Keane WF, Mitch
WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S; RENAAL Study Investigators: Effects of losartan on
renal and cardiovascular outcomes in patients with type 2
diabetes and nephropathy. N Engl J Med 345: 861 869, 2001
Bakris GL, Weir MR, DeQuattro V, McMahon FG: Effects of an
ACE inhibitor/calcium antagonist combination on proteinuria
in diabetic nephropathy. Kidney Int 54: 12831289, 1998
The PROCOPA Study Group: Dissociation between blood
pressure reduction and fall in proteinuria in primary renal
disease: A randomised double-blind trial. J Hypertens 20:
729 737, 2002
Segura J, Campo C, Rodicio JL, Ruilope LM: ACE inhibitors and appearance of renal events in hypertensive nephrosclerosis. Hypertension 38: 645 649, 2001