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Blood pressure control in Diabetic Nephropathy

Why control?

Control of blood pressure is the single most important factor to delay
progression of renal disease in diabetic nephropathy. The UKPDS showed that
controlling the BP is more important than glycemic control in prevention of
both micro and macrovascular complications, this was particularly evident
for the macrovascular complications. So the aim is to prevent progression
of diabetic nephropathy and reduce the incidence of cardiovascular
complications as well as to prevent death.

Goals of BP control

Most international guide lines recommend a level of control below 130/80
in diabetic patients and a level below120/75 in cases associated with more
than 1gm proteinuria

How to control?

The American kidney foundation, and others, issued guide lines to control
the BP. ACE inhibitors or angiotensin receptor blockers should be used as
a first step in view of the role these agents play in delaying progression
of renal diseases in general and diabetic nephropathy in particular.
The second step would be to add a diuretic (frusemide if creatinine is
more than 1.8 mg%) . If still uncontrolled add a long acting calcium
channel blocker. If still the goal is not reached, add a beta blocker
(if the pulse is more than 84) or a long acting calcium channel blocker
of a different category (if the pulse is less than 84). The last step is
to use a direct vasodilator.
Choice of different antihypertensives should take in consideration the
compelling indications and the conditions favoring the use of special
groups of antihypertensives issued by the JNC VI and VII.
It is to be noted that control of the BP is more important than how to
control it.
  1. Factors affecting the choice of antihypertensives
    International recommendations as mentioned.
  2. Compelling and favorable indications in JNC VI and VII.
  3. Special features in diabetics such as autonomic neuropathy,
    impotence, high risk of CVS complications, degree of renal failure,
    metabolic derangement and others.
  4. Economic factors.

ACE inhibitors or Angiotensin receptor blockers (ARBs)

The issue is important because international recommendations did not favor the use of both agents together, at the same time you should start with one of them.

Available data are:

  1. In type I Diabetes with microalbuminuria the use of ACE inhibitors
    is established.
  2. In type I Diabetes with macroalbuminuria and in hypertensive cases
    ACE inhibitors are recommended by most, but not all, authorities.
  3. In type II Diabetes with no renal disease ACE inhibitors are
    recommended because of the overwhelming evidence of their CVS protective
    value (International Diabetes Federation). However evidence is now growing
    for the protective role of ARBs in diabetics (Life and Valiant studies).
  4. In type II Diabetes with microalbuminuria, the use of ARBs is recommended
    (Irma II and Marval studies).
  5. In type II Diabetes with macroalbuminuria and renal impairment, the use of
    ARBs is recommended (Renale and IDNT studies). It is to be noted that in
    both studies cardiac complications and mortality were not different from the
    placebo. It was clear that although ARBs protected the kidney they did not
    protect the patient from death and were no different from other conventional
    antihypertensives.
  6. Renal failure patients, diabetics and non diabetics, are known to be at a
    high risk of CVS complications due to the presence of specific, in addition
    to the conventional risk factors. ACE inhibitors proved to be protective for
    these patients. Studies using ARBs in this field are still progressing.

Dilemma of Life and Renale studies:

The life study clearly showed that Losartan reduced mortality if
compared to Atenolol despite the same BP control.
The Renale study showed that Losartan was not superior to other
antihypertensives in saving patients life. The difference lies in
the different population studied, Renale dealt with patients having
impaired kidney functions where as Life cases had normal functions.
Renal failure patients are known to have different CVS risk factors
profile. It is to be noted that cases in both Renale and IDNT studies
had a creatinine less than 3mg%.

ACE inhibitors or ARBs in type II Diabetes (personal view):

  1. Cases with microalbuminuria and normal kidney functions use ARBs.
  2. Cases with macroalbuminuria and creatinine less than 3mg% use ARBs.
  3. Cases with more advanced renal failure protecting the kidney become
    a less important issue than the occurrence of CVS complications and the
    use of ACE inhibitors would be more logic.
  4. Cases with a very high CV risk, even if creatinine is below 3mg%, the use
    of ACE inhibitor is recommended in view of the proven value of these agents
    in CVS protection.
  5. It is to be noted that in type II diabetics with no renal involvement, ACE
    inhibitors are still the first choice.

List of references

Viberti G, Mogensen CE, Groop LC, Pauls JF. Effect of captopril on
progression to clinical proteinuria in patients with insulin-dependent
diabetes mellitus and microalbuminuria. European Microalbuminuria
Captopril Study Group.


JAMA 1994 Jan 26; 271(4):275-9.

Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, et al. The effects
of dietary protein restriction and blood-pressure control on the progression
of chronic renal disease. Modification of Diet in Renal Disease Study Group.
N Engl J Med 1994 Mar 31;330(13):877-84.

Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, et al. Effects of
losartan on renal and cardiovascular outcomes in patients with type 2
diabetes and nephropathy.
N Engl J Med 2001 Sep 20;345(12):861-9.

Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, et al.
Effect of losartan compared with captopril on mortality in patients
with symptomatic heart failure: randomised trial--the Losartan Heart
Failure Survival Study ELITE II.
Lancet 2000 May 6; 355(9215):1582-7.

Dahlof B, Devereux R, de Faire U, Fyhrquist F, Hedner T, et al.
The Losartan Intervention for Endpoint reduction (LIFE) in Hypertension
study: rationale, design, and methods. The LIFE Study Group.
Am J Hypertens 1997 Jul;10(7 Pt 1):705-13.

Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, et al.
Cardiovascular morbidity and mortality in the Losartan Intervention for
Endpoint reduction in hypertension study (LIFE): a randomized trial
against atenolol.
Lancet 2002 Mar 23; 359(9311):995-1003.

Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, et al.
The effect of irbesartan on the development of diabetic nephropathy in
patients with type 2 diabetes.
N Engl J Med 2001 Sep 20;345(12):870-8.

Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, et al. Renoprotective
effect of the angiotensin-receptor antagonist irbesartan in patients with
nephropathy due to type 2 diabetes.
N Engl J Med 2001 Sep 20;345(12):851-60.

Carey RM, Wang ZQ, Siragy HM. Role of the angiotensin type 2 receptor in
the regulation of blood pressure and renal function.
Hypertension 2000 Jan; 35(1 Pt 2):155-63.

The GISEN Group. Randomised placebo-controlled trial of effect of ramipril
on decline in glomerular filtration rate and risk of terminal renal failure
in proteinuric, non-diabetic nephropathy.
Lancet. 1997 Jun 28; 349(9069):1857-63.

The Seventh Report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure.
JAMA, May 21, 2003-Vol 289, No. 19: 2560.

Omar El-Khashaab, MD
Prof. of Nephrology-Cairo University

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