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Hypertension and Chronic Kidney Disease
a report by
B i f f F ra n k l i n Pa l m e r , M D
Professor of Internal Medicine, Department of Medicine, Division of Nephrology, University of Texas Southwestern Medical Center
Chronic kidney disease is often progressive and can lead to loss of kidney
function and kidney failure, and is strongly associated with cardiovascular
disease. Hypertension is one of the most important determinants in the
development of these end-points. The National Kidney Foundation Clinical
Practice Guidelines for Hypertension currently recommend a goal blood
pressure for all hypertensive patients with chronic kidney disease of
<130mmHg systolic and <80mmHg diastolic.1 According to these
guidelines, the goals of antihypertensive therapy are to reduce the risk for
cardiovascular events and slow the progression of chronic kidney disease.
Hypertension, Renal Autoregulation, and
Renal Disease Progression
The association between hypertension and renal disease progression can at
least in part be traced to the changes in renal autoregulation that typically
accompany a reduction in functional renal mass. With renal injury the
autoregulatory ability of the remaining vasculature becomes impaired in such
a way that intraglomerular pressure begins to vary directly with changes in
systemic arterial pressure.2 This change can be traced to a blunted ability of
the pre-glomerular circulation to either constrict or dilate in response to
changes in renal perfusion pressure. In essence, these vessels take on the
characteristics of a passive conduit. In some patients this impairment is severe
enough that a completely pressure-passive vasculature is present, whereby
any change in mean arterial pressure is matched by a proportional change in
glomerular pressure. As a result, even modest degrees of hypertension lead
to exaggerated increases in glomerular capillary pressure and injury.
A single office blood pressure measurement is unlikely to capture the full
extent to which the systemic blood pressure is transmitted into the
glomerular circulation, since blood pressure exhibits spontaneous, rapid,
and often large fluctuations when continuously monitored. Certain patients
may have well controlled office readings and yet exhibit higher readings at
other times of the day such that the pressure load to the microcirculation is
greater than expected. The lack of a normal nocturnal decline in blood
pressure—often present in black patients, patients with diabetes, and
chronic kidney disease patients—has been associated with a greater
likelihood of renal injury.3 Such disparity in blood pressure measurements
between what is found in the office and what is found at other times of day
has been one of the arguments made against renin–angiotensin blockers
having a blood-pressure-independent effect in reducing cardiovascular
events to include the slowing of chronic kidney disease progression.4–6
Along with fluctuations in blood pressure, the degree to which the
autoregulatory response is impaired is an important factor in determining
the severity of renal injury. The ease with which systemic pressure is
© TOUCH BRIEFINGS 2008
Cardiovascular Risk and Hypertension
transmitted into the microvasculature of the kidney will be proportional to
the degree of impairment. Conditions demonstrated to adversely affect
renal autoregulation and therefore potentially add to the risk for developing
chronic kidney disease in the setting of hypertension include low birth
weight, obesity, insulin resistance, hyperuricemia, hypercholesterolemia,
and increasing age7 (see Table 1).
Impaired renal autoregulation can also explain why hypertensive chronic
kidney disease patients are more likely to develop an increase in serum
creatinine concentration when blood pressure is lowered.8 A blunted ability
of the pre-glomerular circulation to vasodilate in response to a drop in mean
arterial pressure will cause an exaggerated fall in intraglomerular pressure.
This decline in renal function is hemodynamic in origin and does not
represent structural injury to the kidney. The fall in glomerular filtration rate
simply reflects the fact that blood pressure has fallen below the lower limits
of autoregulation. In many patients this initial decline in renal function will
either improve or resolve with long-term blood pressure control. This change
can be traced to improvement in vessel structure and function leading to a
shift in the lower limit of renal autoregulation back toward normal. In those
patients whose renal function remains reduced, the long-term renal outcome
is still improved as a result of better blood pressure control.
Antiproteinuric Therapy in the Management of
Chronic Kidney Disease
Many patients who achieve the goal blood pressure of <130/80mmHg
continue to show evidence of progressive loss of renal function. A readily
Biff Franklin Palmer, MD, is a Professor of Internal Medicine in the
Department of Medicine, Division of Nephrology, at University of
Texas Southwestern Medical Center, where he is also Nephrology
Fellowship Program Director. He is board-certified in internal
medicine and nephrology. Dr Palmer serves as Editor for the
Southwestern Internal Medicine Conference in the American
Journal of Medical Sciences. He is also on the Editorial Board of the
Clinical Journal of the American Society of Nephrology and the
Nephrology Self-Assessment Program (NephSap). He is also a
nephrology committee member for the Medical Knowledge Self Assessment Program (MKSAP 15).
Dr Palmer is a Fellow of the American College of Physicians and the American Society of Nephrology,
and a member of the Texas Medical Association, the International Society of Nephrology, and the
Southern Society for Clinical Investigation. He was awarded the Parkland Memorial Hospital Internal
Medicine Housestaff Outstanding Teacher Award and has received many other teaching awards from
medical student classes at UT Southwestern. Dr Palmer received his medical degree from UT
Southwestern Medical School and completed his residency in internal medicine at Walter Reed Army
Medical Center, Washington, DC. He then went on to complete a research fellowship in the
Department of Nephrology at the Walter Reed Army Institute of Research and a clinical fellowship in
the Division of Nephrology at UT Southwestern Medical Center-Parkland Memorial Hospital.
E: biff.palmer@utsouthwestern.edu
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Cardiovascular Risk and Hypertension
Table 1: Conditions Associated with Endothelial Dysfunction of the
Pre-glomerular Circulation and Impaired Renal Autoregulation
Black race
Low birth weight, intrauterine growth retardation
Aging
Chronic kidney disease
Diabetes
Hypercholesterolemia
Hyperuricemia
Obesity
Table 2: Clinically Available Strategies to Lower Urinary
Protein Excretion
Lower systolic blood pressure to between 110 and 130mmHg systolic
(avoid systolic pressures <110mmHg)#
Pharmacological therapy should be centered around use of ACE inhibitor or
angiotensin receptor blocker
Restrict dietary sodium to <5gm/day
Restrict dietary protein to 0.8gm/kg bodyweight
Use effective diuretic therapy (loop diuretics required when estimated glomerular
filtration rate <30ml/min)
Maximize dose of renin–angiotensin blocker
Use a combination of ACE inhibitor and angiotensin receptor blocker*
Add an aldosterone antagonist to either ACE inhibitor or angiotensin receptor blocker,
but not both
Statin therapy: titrate dose to control LDL cholesterol according to guidelines.
If not dyslipidemic, use starting dose of preferred statin
Discontinue smoking
Weight loss
#Stringent blood pressure control can be associated with an increase in the serum creatinine
concentration. A 30% increase over the baseline value that is stable thereafter does not reflect
structural injury to the kidney but rather is a functional change reflecting favorable effects on
renal hemodynamics, and in particular a lowering of intraglomerular pressure.8
*The serum potassium should be checked within one to two weeks of starting an ACE inhibitor
or an angiotensin receptor blocker or when using these drugs in combination in chronic kidney
disease patients. The risk for hyperkalemia is low when adding an aldosterone receptor blocker
when renal function is normal, but markedly increases with reductions in eGFR and should be
avoided at an eGFR <30ml/min.25
measurable marker that could identify those who remain at high risk for
renal disease progression would be of considerable interest. Ideally, this
same marker could also serve as a guide for the implementation and
titration of additional strategies designed to maximize renoprotection. The
measurement of urinary protein excretion has emerged as a useful tool for
this purpose. Patients excreting large amounts of urinary protein who are
otherwise deemed to be optimally treated should still be considered at high
risk for renal disease progression. Additional measures that decrease urinary
protein excretion will reduce this risk. Maximal reduction in urinary protein
excretion should be a therapeutic goal in the overall strategy to preserve
renal function in patients with proteinuric chronic kidney disease.9
The National Kidney Foundation Kidney Disease Outcomes Quality
Initiative (K/DOQI) working group recommends reducing proteinuria as a
goal of therapy in both diabetic and non-diabetic chronic kidney disease
patients with a spot urine total protein/creatinine >0.5–1mg/mg.1
Assessing the effectiveness of antiproteinuric therapy at lower ratios is
likely to be more difficult due to intra-subject variability in proteinuria.
Nevertheless, in the AASK trial the benefit on renal disease progression
from the initial reduction in proteinuria at six months extended to those
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subjects with baseline protein excretion <300mg/d.10 It is reasonable to
monitor urinary protein excretion on a three- to six-month basis after
having established a baseline value. The initial value allows one to
determine the current risk for renal disease progression and the need for
implementation of antiproteinuric therapies. Subsequent measurements
gauge the effectiveness of the therapy employed as well as guide further
titration when needed. Clinical tools to lower urinary protein excretion are
given in Table 2.
Stringent Blood Pressure Control
The initial step in reducing urinary protein excretion in chronic kidney
disease patients is to establish and maintain stringent blood pressure
control. Blood pressure reduction per se will exert an antiproteinuric effect
even when accomplished with agents not typically deemed to be
renoprotective. As previously discussed, current guidelines suggest blood
pressure should be lowered to <130/80mmHg in patients with chronic
kidney disease. An even lower systolic pressure may be of benefit in
slowing progressive renal disease in patients with a spot urine total
protein:creatinine ratio of >0.5–1mg/mg.11,12 Those with lesser amounts of
proteinuria derive no additional benefit. There is evidence that lowering
systolic blood pressure to <110mmHg should be avoided as there may be
a higher risk for kidney disease progression.13 The precise reason for this
adverse effect is unclear, but may relate to an impaired autoregulatory
response of a diseased kidney to decreases in systemic blood pressure.
Blood pressure control should be centered around a renin–angiotensin
system antagonist since these agents consistently demonstrate a greater
antiproteinuric effect than can be explained by blood pressure reduction
alone.11 Either an angiotensin-converting enzyme (ACE) inhibitor or an
angiotensin receptor blocker can be utilized for this purpose as there is no
convincing evidence that one drug class exerts a greater antiproteinuric
effect compared with the other at comparable doses and similarly
controlled blood pressure.14,15
Restrict Dietary Sodium and Use Effective Diuretic Therapy
A high dietary sodium intake is associated with worsening urinary protein
excretion, whereas sodium restriction reduces proteinuria. Restricting
dietary salt intake to 80–110mmol/day is a useful goal. Compliance can be
verified by measuring urinary sodium in a 24-hour urine collection. Sodium
restriction is of particular relevance for patients taking ACE inhibitors,
angiotensin receptor blockers, and non-dihydropyridine calcium channel
blockers since increased sodium intake can abolish the antiproteinuric
effect of these drugs. In contrast, sodium restriction augments the
antiproteinuric effect of these agents to an extent than cannot be
accounted for by blood pressure reduction alone.16 Effective diuretic
therapy also enhances the antiproteinuric effect of renin–angiotensin
blockers and can restore the antiproteinuric effect that is lost under
conditions of high sodium intake. Thiazide diuretics are useful for this
purpose until the estimated glomerular filtration rate falls to <30ml/min, at
which point loop diuretics should be utilized. A combination of salt
restriction and effective diuretic therapy will reduce urinary protein
excretion to a greater extent than either intervention alone.
Use Moderate to High Doses of Renin–Angiotensin Blockers
The Working Group of the K/DOQI recommends that moderate to high
doses of ACE inhibitors or angiotensin blockers be used in chronic kidney
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Hypertension and Chronic Kidney Disease

disease patients.1 Higher doses of these agents generally exert greater
antiproteinuric effects even when there is no further change in systemic
blood pressure. Although not yet recommended, small studies have
employed supratherapeutic doses of angiotensin receptor blockers in an
attempt to determine the ceiling at which no further reductions in urinary
protein occur. Doses of up to 900mg/day of irbesartan, 64mg/day of
candesartan, and 160mg/day of telmisartan provide further blood-
pressure-independent drops in urinary protein excretion in the absence of
significant side effects.17
Combined Use of Renin–Angiotensin–Aldosterone Blockers
There are numerous small trials demonstrating an additive antiproteinuric
effect of ACE inhibitors and angiotensin receptor blockers used
together.18 In many of these studies blood pressure is lower in the
combination groups, making it difficult to establish whether the benefit
is due to the drug combination per se or simply better blood pressure
control. In one long-term study a combination of trandolapril and
losartan reduced urinary protein excretion to a greater extent than either
drug used alone and in a setting where reduction in blood pressure was
similar.19 Importantly, renal function was better preserved in the
combination group. It is not clear whether the combination of an ACE
inhibitor and angiotensin receptor blocker is more renoprotective
compared with either of the individual agents used alone but at high
doses. In patients with inadequate blood pressure control, the
combination may be preferred so as to capitalize on the blood-pressure-
lowering effect of the drugs.
Monotherapy with either an ACE inhibitor or an angiotensin receptor
blocker may be sufficient to treat patients with microalbuminuria as
combination therapy appears to offer no additional antiproteinuric effect in
this setting.20 High doses of the single agent should be utilized in order to
maximize renal protection, as has been demonstrated in patients with type
2 diabetes and microalbuminuria.21 Limited evidence suggests the addition
of spironolactone or eplerenone to either an ACE inhibitor or an angiotensin
receptor blocker can further reduce urinary protein excretion by an amount
not accounted for by blood pressure reduction alone.22
Direct Renin Inhibitor Therapy in Chronic Kidney Disease
Aliskerin is a direct renin inhibitor that blocks the catalytic site of renin,
thereby reducing formation of angiotensin 1 from angiotensinogen and
hence the downstream effector angiotensin II. Pre-clinical data suggest the
drug provides similar renal protection to an ARB in a rat model of
hypertensive nephropathy.23 In a recently completed study, 599 patients with
diabetic nephropathy all treated with 100mg daily of losartan were
randomized to receive either placebo or aliskerin. Those subjects who
received aliskerin demonstrated a 20% greater reduction in proteinuria
compared with those who received placebo.24
Hyperkalemia Complicates the Use of
Renin–Angiotensin Blockade
Use of ACE inhibitors and ARBs in patients with chronic kidney disease can be
associated with hyperkalemia. As with a rise in the serum creatinine
concentration, many physicians respond to even mild increases in the serum
potassium by immediately discontinuing these drugs without first considering
steps that might be taken to minimise this complication. In many instances,
physicians are reluctant to even initiate such therapy simply because the
patient has an elevated creatinine concentration. Such an approach is strictly
to the patient’s disadvantage, since patients with more advanced renal
insufficiency derive a greater amount of protection from renal disease
progression with these drugs. While close monitoring is required, several steps
can be taken to minimize the likelihood of developing hyperkalemia.25
One should review the patient’s medication profile and wherever possible
discontinue drugs that can impair renal potassium excretion. Non-steroidal
anti-inflammatory agents, either prescribed or those taken over-the-counter,
are common offenders in this regard. The patients should be placed on a
low-potassium diet with specific counseling against the use of potassium-
containing salt substitutes. Diuretics are particularly effective in minimizing
hyperkalemia. In patients with a serum creatinine <1.8mg/dl, thiazide
diuretics can be used, but with more severe renal insufficiency loop diuretics
are required. In chronic renal failure patients with metabolic acidosis
(bicarbonate concentration <20mEq/l), administration of sodium bicarbonate
should be given. Decreasing the dose of the renin–angiotensin blocker or
switching to one that is not totally dependent on renal excretion may be of
help. Intermittent use of a potassium-binding resin can be tried; however,
this drug is poorly tolerated when used on a chronic basis and has been
associated with gastrointestinal ulceration.
Conclusion
Hypertension is a major risk factor for the development of cardiovascular
complications, including the development and progression of chronic
kidney disease. Stringent blood pressure control centered on the use of a
renin–angiotensin receptor blocker is a useful starting point to slow the
progression of chronic kidney disease. Patients excreting large amounts of
urinary protein who are otherwise deemed to be optimally treated should
still be considered at high risk for renal disease progression. Maximal
reduction in urinary protein excretion should be a therapeutic goal in the
overall strategy to preserve renal function in patients with proteinuric
chronic kidney disease. Small and non-progressive increases in the serum
creatinine concentration accompanying better blood pressure control do
not reflect structural injury to the kidney, but rather reflect a favorable effect
on renal hemodynamics, in particular a lowering of intraglomerular
pressure. By taking several precautions the majority of patients at risk for
hyperkalemia can be successfully treated rather than unnecessarily being
labeled as intolerant to these drugs. ■

1. Am J Kidney Dis, 2004;43(5 Suppl. 1):S1–290. 10. Lea J, et al., Arch Intern Med, 2006;165:947–53. 19. Nakao N, et al., Lancet, 2003;361:117–24.
2. Palmer BF, Am J Med Sci, 2001;321:388–400. 11. Sarafidis P, et al., Am J Kidney Dis, 2007;49:12–26. 20. Bakris G,et al., Kidney Int, 2007;72:879–85.
3. Thompson A, Pickering T, Kidney Int, 2006;70:1000–1007. 12. Peterson JC, et al., Ann Intern Med, 1995;123:754–62. 21. Makino H, et al., Diabetes Care, 2007;30:1577–8.
4. Griffin K, Bidani A, Clin J Am Soc Nephrol, 2006;1:1054–65. 13. Jafar TH, et al., Ann Intern Med, 2003;139:244–52. 22. Bomback A, et al., Am J Kidney Dis, 2008;51:199–211.
5. Alicic R, Tuttle K, Curr Htn Res, 2007;9:393–402. 14. Matcher D, et al., Ann Intern Med, 2008;148:16–29. 23. Gradman A, et al., Curr Opin Pharmacol, 2008;8:120–26.
6. Sica DA, Curr Hypertens Rep, 2008;10:415–20. 15. Kunz R, et al., Ann Intern Med, 2008;148:30–48. 24. Parving H, et al., N Engl J Med, 2008;358:2433–46.
7. Palmer BF, Am J Med Sci, 2004;328:330–43. 16. Vogt L, et al., J Am Soc Nephrol, 2008;19:999–1007 25. Palmer BF, N Engl J Med, 2004;351:585–92.
8. Palmer BF, Engl J Med, 2002;347:1256–61. 17. Palmer BF, Am J Nephrol, 2008;28:381–90.
9. Palmer BF, Am J Nephrol, 2007;27:287–93. 18. MacKinnon M, et al., Am J Kidney Dis, 2006;48:8–20.

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