Download ACE Inhibitors or ARBs

In The Name of GOD
Diabet and Hypertension in
CKD Patients
Dr. Sahar Vahdat, Nephrologist
Diabetes
The prevalence of DM contibues to rise with
an expected 370 million to be affected in 2030
Leading cause of ESRD in Western countries
Diabetic Renal Disease
 Can develop in the course of both Type I & Type II
diabetes
 The proportion of patients who develop proteinuria and
elevated serum Cr is related to duration of diabetes
 Overt diabetic nephropathy is characterized by persistent
albuminuria 300mg/24h on at least 2 occasions separated
by 3- 6 months
Prevalent counts &
adjusted rates of
ESRD, by primary
diagnosis
Figure 1.15 (Volume 2)
Pathogenesis of Diabetic Nephropathy
Haemodynamic changes- increased GFR- afferent
arteriolar vasodilatation mediated by range of
vasoactive mediators
Renal hypertrophy- plasma glucose stimulates
several growth factors within the kidney
Mesangial expansion & nodule formation
Proteinuria
Tubulo-interstitial fibrosis
Normal glomerulus
Kimmelstiel-Wilson Nodule
Diagnosis
 History of Diabetes Mellitus
 Proteinuria
 Presence of other diabetic complications eg retinopathy
 Renal Impairment in later stages
 Note no haematuria – if present may require renal
biopsy
Albuminuria
Normoalbuminuria <30mg/g creatinine
Microalbuminuria 30-300 mg/g creatinine
Macroalbuminuria >300 mg/g creatinine
Time Course of Type 2 Diabetic Renal Disease
Microalbuminuria
Proteinuria
ESRD
Cardi ovascular Morbidity and Mortality
Early Stage
Late Stage
Kidney Disease
End Stage
Proteinuria in Diabetics
The greater the proteinuria, the higher the CV risk
Prevention & Treatment
Glycaemic control
Maintain tight glycaemic control

(HbA1c < 7)
Anti-hypertensive therapy
Tight BP control
ACE inhibitors and ARBs
Lipid control
Glycemic Targets
cardiovascuiarDisease (CVD) & Diabetes
2015 American Diabetes Association (ADA) Diabetes
Guidelines Summary Recommendations from NDEI
 Microvascular Complications & Foot Care
2015 American Diabetes Association (ADA) Diabetes
Guidelines Summary Recommendations from NDEI
Immunizations
Factors favouring the diagnosis of classical diabetic
nephropathy or alternative renal diagnoses
Conditions that can cause transient albuminuria
Screening for Albuminuria
When screening for albuminuria, the test of choice is the random urine
albumin-to-creatinine ratio (urinary ACR).
The 24-hour urine collection for protein/albumin remains the gold
standard; however, it is cumbersome to implement on a large scale and
is often performed incorrectly.
The random urine for albumin is insufficient, as the urinary albumin
concentration can vary due to urine concentration. A random urine
ACR predicts 24-hour urinary albumin excretion sufficiently well and
is the test of choice for screening for albuminuria.
 There is substantial day-to-day variability in albuminuria
 . In addition, transient increases in albuminuria can be
provoked by a number of factors. When such conditions are
present, screening for kidney disease should be delayed to
avoid false positives.
 Furthermore, diagnosing a person as having albuminuria
requires the elevated urinary albumin level to be persistent
 . At least 2 of 3 urine samples over time exhibiting elevations
in urinary albumin levels are required before it is considered to
be abnormal.
Estimation of GFR
The serum creatinine is the most common measurement of
kidney function; however, it can inaccurately reflect renal
function in many scenarios, particularly in extremes of
patient age or size. Indeed, in people with diabetes, the GFR
usually will be less than half of normal before the serum
creatinine exceeds the lab normal range.
Relative risk of chronic kidney disease (CKD).
Treatment Algorithm
for Diabetic
Nephropathy
 Despite the strong interplay between diabetes and CKD, the
management of patients with diabetes and CKD stage 3b or
higher (eGFR <45 mL/min) remains problematic.
 Many guidance-providing documents have been produced
on the management of patients with diabetes to prevent or
delay the progression to CKD, mostly defined as the
presence of micro and macro-albuminuria.
 However, none of these documents specifically deal with
the management of patients with CKD stage 3b or higher.
Key risk factors for diabetic nephropathy include
long duration of diabetes, poor glycemic control,
hypertension, male gender, obesity and cigarette
smoking. Many of these factors are modifiable.
 The earliest stage of diabetic nephropathy is hyperfiltration,
where the glomerular filtration rate (GFR) is significantly
higher than normal.
 Identification of hyperfiltration is not clinically useful, as it
is difficult to determine from routine testing.
 Persistent albuminuria is considered the earliest clinical sign
of diabetic nephropathy. Initially, small amounts of albumin
are leaked, below the detection threshold of a urine dipstick.
This stage is referred to as “microalbuminuria.”
 This can worsen so that the urinary albumin excretion is sufficiently
high to be detectable by a urine dipstick, a stage known as “overt
nephropathy.”
 The rate of progression from normoalbuminuria to
microalbuminuria then to overt nephropathy usually is slow,
typically taking 5 years or longer to progress through each stage.
During the early stages of diabetic nephropathy, the rate of loss of
renal function is relatively slow (1 to 2 mL/min/1.73 m2 per year)
and not impressively higher than what is seen in the general
population (0.5 to 1 mL/min/1.73 m2 per year) However, late in the
overt nephropathy phase, the rate of decline of renal function can
accelerate (5 to 10 mL/min/1.73 m2 per year).
 Thus, significant renal dysfunction is not usually seen until late in
the course of diabetic nephropathy.
 It is important to note that the rate of progression can vary
between individuals, and that the clinical markers of the
disease (i.e. estimated glomerular filtration rate [eGFR],
urinary albumin levels) do not always correlate well with the
severity of renal disease seen on biopsy.
 Additionally, aggressive control of blood pressure (BP) and
glycemia, and the use of renal protective drugs can slow or
stop progression of diabetic nephropathy.
Key Messages
 Identification of chronic kidney disease (CKD) in diabetes requires
screening for proteinuria, as well as an assessment of renal function.
 All individuals with CKD should be considered at high risk for
cardiovascular events and should be treated to reduce these risks.
 The progression of renal damage in diabetes can be slowed through
intensive glycemic control and optimization of blood pressure.
Progression of diabetic nephropathy can be slowed through the use
of medications that disrupt the renin-angiotensin-aldosterone
system.
Renin-Angiotensin System Blockade
in Prevention
 The role of blockade of the renin-angiotensin system (RAS) in
normotensive, normoalbuminuric diabetic patients for the
primary prevention of DN is unproved and cannot be
recommended at this time.
 Most patients with diabetes do not develop DN, even after long
periods of uncontrolled hyperglycemia, and there are hazards
with the use of RAS-blocking drugs, including their potential
teratogenicity in pregnancy.
 In hypertensive diabetic patients, an angiotensin-converting
enzyme (ACE inhibitor) or an angiotensin receptor blocker ARB
is effective as a first-line antihypertensive agent.
Nonpharmacologic Interventions
 For all diabetic patients, emphasis should be placed on
lifestyle modification to lower the risk of diabetic kidney
disease and CV events, including dietary restriction of salt and
saturated fat, weight reduction and exercise as appropriate, and
smoking cessation.
 Smoking in particular is an independent risk factor for the
development of nephropathy in type 2 diabetes and is
associated with an accelerated loss of renal function.
Treatment of Diabetic Patients with
Microalbuminuria
 Overt nephropathy for diabetic patients with incipient or
established DN, the optimal therapeutic approach to reduce the
rate of progression of nephropathy and to minimize the risk for
CV events involves aggressive management of hypertension
with emphasis on a RAS blocker, combined with management
of dyslipidemia, hyperglycemia, and albuminuria, as well as
diet modification, exercise, and smoking cessation
 In general, patients with DN require multiple antihypertensive
agents (including RAS-blocking agents) to achieve BP goal,
intensive insulin therapy in type 1 diabetes, two or more drugs for
glucose control in type 2 diabetes, at least one lipid-lowering agent,
and an aspirin or other antiplatelet agent for CV protection.
 One obstacle to achieving adherence is the number of medicines and
the complexity of these regimens.
 Therefore, treatment of patients with DN needs to be individualized
and requires considerations of the cost, side effects, and convenience
of the drug regimen. Regular monitoring of UAE and serum
creatinine concentration to assess response to therapy and
progression of disease is required
Renin-Angiotensin System Blockade
in Treatment
 In diabetic patients with established DN, RAS blockade
with ACE inhibitors or ARBs confers preferential
renoprotection that is independent of BP reduction.
Intraglomerular hemodynamic and nonhemodynamic
renal effects of angiotensin II (Ang II) best explain the
observed renoprotection
Dosing and Adverse Effects Associated
with ACE Inhibitors and ARBs
 The antiproteinuric effect of ACE inhibitors and ARBs is at
least in part independent of blood pressure reduction, and in
individual patients, proteinuria may continue to respond to
dose escalations beyond those recommended for BP control
 Unfortunately, maximal dosing of ACE inhibitors or ARBs
may be limited by side effect reproductive age, counseling
about pregnancy prevention and contraceptive use should
begin before ACE inhibitor or ARB is started.
 Serum creatinine concentration may increase up to 30% in
proteinuric patients with renal impairment and therefore the ACE
inhibitor should not necessarily stopped in these patients.
 Increases in serum creatinine concentration above 30% after
initiation of an ACE inhibitor should raise the suspicion of renal
artery stenosis. Aggressive dose increments of ACE inhibitors or
ARBs, especially in conjunction with diuresis, can precipitate acute
kidney injury (AKI).
 In advanced CKD and aggressive sodium restriction, although ACE
inhibitors and ARBs are not contraindicated, the de novo
introduction of these agents or injudicious dose increments may
precipitate the need for dialysis prematurely, so some caution is
appropriate.
Combination Therapy with ReninAngiotensin System Antagonists
 In both type 1 and type 2 diabetic patients with nephropathy,
results of several earlier small trials suggested that the
combination of an ACE inhibitor and an ARB is more effective in
reducing BP and proteinuria than is either drug alone
 In summary, evidence from clinical trials suggest caution in the
use of RAS antagonists in combination, which is presumably not
superior to maximum tolerated dose of the monotherapies.
Other Antihypertensive and
Antiproteinuric Agents
Calcium Channel
Blockers
Nondihydropyrid
ine
Dihydropyrid
ine
Diuretics and Low
Sodium Intake
β-Blockers
Diuretics and Low Sodium
Intake
 The antiproteinuric effects of RAS blockade are enhanced by sodium
restriction and diuretic use. Patients receiving ACE inhibitors or ARBs
should be instructed to take a low-sodium diet (e.g., <2 g sodium/day).
 The combination of a loop diuretic or a thiazide diuretic with agents
that block the RAS may be more effective than either type of treatment
alone for lowering blood pressure and proteinuria.
 Selective aldosterone receptor antagonists (e.g., spironolactone,
eplerenone) have been shown to reduce proteinuria when used alone
and have an additive effect on proteinuria when used with ACE
inhibitor or ARB..
Calcium Channel Blockers
 Dihydropyridine calcium channel blockers (dCCBs; e.g.,
nisoldipine, nifedipine, amlodipine) may be used as additional
antihypertensive agents, but they have not been shown to reduce
albuminuria or to slow the progression of renal disease.
 Nondihydropyridine calcium channel blockers (ndCCBs; e.g.,
diltiazem, verapamil) have been shown in some studies to have
beneficial antiproteinuric effects. Taken together, these findings
suggest ndCCBs are reasonable agents for BP control and can be
used in combination with a RAS antagonist in patients with DN.
β-Blockers
 Classic β-adrenergic blockers have adverse metabolic effects and
are therefore undesirable in diabetic patients, but this is no longer
true for the novel β-blockers (e.g., carvedilol, nebivolol).
 Despite insufficient controlled evidence, β-blockade appears to
be useful because of the extremely high CV risk in diabetic
patients with nephropathy and can be used in combination with
ACE inhibitors or ARBs but not ndCCBs to achieve optimal
BP control
Glycemic Control
 Most of the evidence favoring strict glycemic control comes
from studies of patients with normoalbuminuria or early stages
of DN.
 For type 2 diabetic patients with established DN, large trials
(e.g., Kumamoto study, ADVANCE, ACCORD trial) suggest
that strict glycemic control may provide some renoprotection
but does not protect against macrovascular complications.
 Thus, glucose-lowering treatment must be individualized in type 2
diabetes. It should be more aggressive in young patients with short
duration of diabetes, high life expectancy, and low risk of
hypoglycemia.
 A more cautious approach is sensible in the elderly patient who has
longstanding diabetes, has preexisting CV problems, gains weight
with insulin, and is susceptible to hypoglycemic episodes.
 Current guidelines recommend lifestyle intervention first and
suggest the addition of basal insulin (most effective), sulfonylurea
(least expensive), or thiazolidinediones (no hypoglycemia) if HbA1c
values still exceed 7%.
Treatment
 Progressive CKD leads to changes in insulin and carbohydrate
metabolism.
 As glomerular filtration rate (GFR) continues to decline,
especially below 60 ml/min/1.73 m2, regular review of the
patient’s oral antidiabetic agents or insulin doses is essential
because these may need to be reduced or even stopped
altogether, a result of accumulation of the drugs and their
metabolites, which can have various adverse effects.
Biguanides
 The only drug in the biguanide class in contemporary use is
metformin, which works as an insulin sensitizer
 The American Diabetes Association (ADA) and the European
Association for the Study of Diabetes (EASD) state that the
use of metformin is safe down to an estimated GFR (eGFR) of
30 ml/min/1.73 m2, with dose reductions advised with eGFR
less than 45 ml/min/1.73 m2.
Sulfonylureas
 A class of insulin secretagogues, the older generation of sulfonylureas
(tolbutamide, glibenclamide) are long acting and almost exclusively
excreted by the kidneys and thus are best avoided in CKD patients.
 Newer agents are of shorter duration and primarily metabolized by the
liver, although most metabolites are subject to renal clearance. The
metabolites of gliclazide and glipizide are inert or only weakly active, so
these particular sulfonylureas can be used even in patients with ESRD
receiving dialysis.
 Their use does carry the risk of hypoglycemia, especially as GFR declines
and insulin clearance decreases. Sulfonylureas are highly protein-bound but
can be displaced into circulation by other drugs used in diabetic patients
(e.g., salicylates, β-blockers, fibric acid derivatives), further contributing to
hypoglycemia.
Thiazolidinediones
 The
thiazolidinediones
are
peroxisome
proliferator-activated
receptor (PPAR) modulators, which work to increase insulin
sensitivity.
 Their use is limited by resultant weight gain and fluid retention
through
transcriptional
upregulation
of
amiloride-sensitive
sodium(Na+) channels in renal tubules, which is problematic in a
population already prone to CVD and heart failure.
 Rosiglitazone was withdrawn from the market because of the
suggestion of an increased risk of myocardial infarction with its use,
although pioglitazone remains in use.
Meglinitides
 The main drugs in the meglinitide class, nateglinide and
repaglinide, are primarily metabolized in the liver and act as
insulin secretagogues.
 Repaglinide is safe to use in diabetic patients with advancing
renal failure because it is converted to inactive metabolites and
mainly excreted in bile, with less than 10% of the parent drug
appearing in the urine, so no dose adjustments are deemed
necessary.
 More than 80% of nateglinide is excreted in the urine, and thus
it should only be used cautiously, if at all, in advanced CKD.
Insulin
 Exogenous insulin, unlike endogenously secreted insulin, which
undergoes first-pass metabolism in the liver, is primarily eliminated by
the kidneys through free filtration and secretion into the renal tubules,
before reuptake and degradation by peritubular cells.
 As GFR falls below 60 ml/min/1.73 m2, insulin requirements in both
type 1 and type 2 diabetic patients progressively fall, by up to 40% to
50%, regardless of residual insulin secretion in type 2 patients. This
decline is especially marked as GFR falls below 20 ml/ min/1.73 m2
and approaches ESRD.
 This helps to explain the phenomenon of hypoglycemia in nondiabetic
patients with advanced CKD, although importantly, the kidney is an
important site for gluconeogenesis, which can fail as CKD progresses.
Insulin resistance itself results from CKD.
 Type 2 diabetic patients, when requiring insulin, usually start
on once-daily or twice-daily, long-acting or intermediateacting insulin, if necessary moving onto mixed formulations
(fixed percentages of short-acting and longeracting insulins) as
in type 1 patients.
Hypertension in CKD
CKD and hypertension (HTN) are closely associated with an
overlapping and intermingled cause and effect relationship.
Declines in kidney function are typically associated with rises in
blood pressure (BP), and sustained elevations in BP hasten the
progression of kidney function decline.
Pathophysiology of Hypertensive
Renal Damage
 The direct adverse consequences of hypertension on any
vascular bed are expected to be a function of the degree to
which it is exposed to the increased pressures.
 The pathogenetic determinants of hypertensive renal damage
can thus be broadly separated into 3 categories:
(1) the systemic BP “load”
(2) the degree to which such load is transmitted to the renal
vascular bed
(3) local tissue susceptibility to any given degree of barotrauma.
BP Load and Its Transmission to the
Renal Microvasculature
 Normally, increases in systemic BP, episodic or sustained, are prevented
from fully reaching the renal microvasculature by proportionate
autoregulatory vasoconstriction of the preglomerular vasculature such that
renal blood flow and glomerular hydrostatic pressures (PGC) are maintained
relatively constant
 These autoregulatory responses provide the primary protection against
hypertensive renal damage.,therefore only benign nephrosclerosis is
observed; however, if this threshold is exceeded, acute disruptive injury
(malignant nephrosclerosis) is expected to result despite intact
autoregulation.
 However, once vascular injury develops, autoregulatory responses can be
secondarily compromised and result in the amplification of renal damage.
Local BP-Independent Determinants of
Tissue Susceptibility
 of the local mechanisms, the BP-independent tissue damage
promoting effects of angiotensin II and, more recently,
aldosterone have received the greatest emphasis.
Circadian Rhythm of BP in Patients
With CKD
 In healthy individuals, BP falls by 10% to 20% during sleep. A
fall in nocturnal BP characterizes a normal circadian pattern of
BP.
 Individuals whose BP fails to drop or, instead, rises at night are at
an increased risk of death compared with dippers.
 In addition, mean nocturnal systolic BP predicts ESKD or death,
and nondipping is associated with the severity of interstitial
fibrosis and tubular atrophy by kidney biopsy.
 Therefore, dipping patterns are blunted in individuals with CKD
is concerning and particularly relevant for management of HTN
in patients with CKD.
Night-time Antihypertensive Medication
Dosing
 Multiple clinical trials have shown an improvement in
nocturnal dipping of BP by dosing at least 1 antihypertensive
medication at bedtime, and night-time medication dosing has
been associated with reduced cardiovascular risk.
The Central Role of Salt in CKD and HTN
 Experimental animal models have shown that HTN brought on
by inducing kidney damage is associated with a decreased
ability of the kidney to remove salt.
 Many conditions associated with CKD can impair salt
excretion, including reduced renal mass, sympathetic nervous
system activation, reninangiotensin-aldosterone imbalance,
altered sodium chloride handling in the distal nephron,
endothelial dysfunction, or some combination of the earlier
mentioned conditions.
 High dietary salt intake not only exacerbates HTN in patients
with CKD but also has the potential to directly worsen kidney
function. receiving a high salt diet show sustained increases in
kidney levels of transforming growth factor-β, polypeptides
associated with kidney fibrosis.
 High salt diet blunts kidney autoregulation, which exposes the
glomerulus to higher filtration pressures. Over time, the high
glomerular filtration pressure leads to glomerular sclerosis and
nephron loss.
 The associated worsening of both HTN and CKD in the setting of
high salt intake highlights the importance of salt restriction in the
management of HTN in patients with CKD
 Review of evidence base supported a lower BP goal of less than
130/80 mm Hg for individuals with CKD and moderate-to-severe
albuminuria (eg, urine albumin-to-creatinine ratio > 30 mg/g)
either with or without diabetes mellitus.
 In a cohort of over 650,000 Veteran Americans with CKD,
extremes of both high and low BPs were associated with
increased morality, with the highest mortality for patients with
high pulse pressures.
 it may not be advantageous to achieve an ideal systolic BP (<130
mm Hg) in patients who have existing low diastolic BP (<70 mm
Hg).
 CKD alone can lead to antihypertensive medication resistance;
however, patients who remain uncontrolled on ideal doses of 3
different medication classes, including a diuretic, should undergo
an evaluation for a separate secondary cause of HTN.
 In some forms of CKD, HTN may be the earliest sign of kidney
dysfunction (eg, polycystic disease) and appropriate HTN management
reduces both cardiovascular and kidney outcomes.
 Impaired dipping of BP during sleep, salt-sensitive HTN and
exaggerated BP responses to restrictions in dietary salt all highlight the
importance of salt in patients with CKD and HTN.
 In addition to the well-established use of an ACEI or angiotensin
receptor blocker, dietary salt restriction and appropriate diuretic therapy
make up the mainstay of HTN treatment in patients with CKD.
 Lastly, future clinical practice guidelines may recommend bedtime
dosing of 1 or more antihypertensive medications in patients with
CKD.
 Ambulatory BP monitoring is needed to detect masked HTN and nondipping, which are common in CKD.
Treatment
 Agents that not only lower BP but also reduce proteinuria are
recommended as first-line therapy for most patients with CKD and
HTN;
 data indicate there may be significant long-term benefits in both
cardiovascular and renal outcomes when proteinuria is decreased.
 Several classes of antihypertensive agents may have a role in the
treatment of CKD and HTN. Agents that target the reninangiotensinaldosterone system (RAAS), such as angiotensinconverting enzyme (ACE) inhibitors or angiotensin receptor
blockers
(ARBs),
are
generally
considered
first-line
antihypertensive therapy for this patient population.
ACE Inhibitors or ARBs
 Studies have shown that antihypertensive agents that target the
renin-angiotensin system prevent kidney decline more so than other
agents, even when achieving similar BP goals.
 These results were found primarily in patients with proteinuria,
whereas the benefit was less substantial for those without
proteinuria.
 Based on these findings, guidelines recommend ACE inhibitor or
ARB therapy as first-line treatment for those with diabetes or those
presenting with nondiabetic kidney disease, HTN, and proteinuria.
 Data indicate that ACE inhibitors and ARBs are equally effective in
lowering BP and reducing proteinuria.
 A recent meta-analysis suggests that ACE inhibitor therapy may
provide superior benefit over ARB therapy for the treatment of
HTN due to a 10% reduction in all-cause mortality.
 These results were determined for patients with HTN and did not
apply to patients with additional comorbidities such as CKD.
Therefore, selection of one agent over another will depend on
patient-specific factors such as potential for side effects and cost.
 Treatment with both an ACE inhibitor and an ARB is not
recommended, as this combination has been shown to worsen
kidney function.
 Combination ACE inhibitor and ARB therapy did not reduce
cardiovascular mortality or morbidity in comparison to
monotherapy of an ACE inhibitor.
 ACEinhibitors and ARBs are generally well tolerated. ACE
inhibitors may cause a dry cough, which unfortunately often
requires a change in therapy.
 ARBs are not associated with dry cough.
 Angioedema is very rare; however, patients started on ACE
inhibitors or ARBs should be informed of the signs and
symptoms that may present with angioedema.
 Inform patients that angioedema is unlikely, but if they
experience swelling in their face (often including the eyelids)
and/or extremities, they should discontinue treatment and seek
medical attention immediately
Salt Restriction
 The available evidence supports a large component of salt
sensitivity to HTN in patients with CKD. Therefore, educating
patients with CKD on a low salt diet is critical to achieving BP
control while maintaining a simple BP medication regimen.
 A modest dietary sodium restriction can enhance the effects of
antihypertensive and antiproteinuric medications like
angiotensin-converting
enzyme
inhibitors
or
angiotensin receptor blockers and diuretics when
treating HTN in CKD.
 Concerns have been raised about potential risks from overly
restricting dietary sodium the evidence was insufficient to
recommend restricting daily sodium intake further than 2.3
g/d.
 The committee did identify a subgroup at risk for adverse
events from a low sodium diet (eg, individuals with heart
failure with a reduced ejection fraction and receiving
aggressive therapeutic regimens); however, this does not apply
to most individuals with HTN and CKD, who are at risk for
salt-sensitive HTN.
Diuretic Use in Advanced CKD
 In general, as GFR falls, higher doses of diuretics are needed
to achieve a natriuretic response. Diuretic dosing can be
particularly challenging in late stages of CKD when the risk of
over diuresis and its associated hastening of progression to
dialysis outweighs the benefit of improved BP control.
 This is further complicated in patients with hypoalbuminemia
as less protein-bound loop diuretic is available for tubular
secretion.
 Furthermore, the short-acting effect of many loop diuretics
hinders their efficacy in long-term BP control.
 For all these reasons, clinicians have reconsidered the use of
thiazide diuretics as an alternative or additional medication to
the use of loop diuretics in advanced CKD (estimated GFR <
30 mL/min/1.73 m2) where they traditionally have been
thought to be ineffective.
 Chlorthalidone, the long-acting thiazide used in many of the
large clinical trials of HTN, has twice the potency of
hydrochlorothiazide at similar doses and may hold some
efficacy in advanced CKD.
 The combination of a thiazide and a loop diuretic may be most
effective in patients with excess volume.
Mineralocorticoid Antagonist Use in CKD
 Impressive reductions in BP for individuals receiving 3 or more
antihypertensive medications have made mineralocorticoid
antagonists an important fourth-line BP agent in the treatment of
resistant HTN.
 Patients in later stages of CKD are likely to meet the classification
of resistant HTN; however, risks of hyperkalemia and acute
kidney injury have limited mineralocorticoid antagonist use in
advanced CKD.
 In proteinuric CKD and HTN, spironolactone effectively reduces
both BP and urine protein levels.
 However, caution is advised with starting spironolactone in
patients who have a baseline serum potassium greater than 4.6
mEq/L. Spironolactone is contraindicated in patients with acute
kidney injury and creatinine clearances less than 10 mL/min.
Eplerenone, a more selective mineralocorticoid antagonist, is
contraindicated for use when creatinine clearance falls less than
30 mL/min.
 Finerenone, which binds the mineralocorticoid receptor with a
higher affinity than eplerenone, is currently undergoing clinical
trials for Federal Drug Administration approval in the treatment
of heart failure and proteinuric diabetic nephropathy.
Calcium Channel Blockers
 Calcium channel blockers (CCBs) are considered second- or
third-line therapy in the treatment of HTN in patients with CKD.
 While there may be no difference in the effect on BP lowering
between nondihydropyridine CCBs (ND-CCBs; e.g., diltiazem,
verapamil) and dihydropyridine CCBs (e.g., amlodipine,
nifedipine), ND-CCBs have been shown to significantly reduce
proteinuria either when used alone or in combination with an
ACE inhibitor or an ARB.
 Because of their potential to reduce proteinuria, in addition to
their antihypertensive effects, ND-CCBs should be considered as
second- or third-line therapy in patients with diabetic CKD or
nondiabetic CKD with proteinuria.
 Dihydropyridine CCBs can be used as second-line agents in
patients with nondiabetic CKD without proteinuria.
 Common adverse effects include edema and constipation with
ND-CCBs (especially verapamil) and flushing and peripheral
edema with dihydropyridine agents.
Beta-blockers
Data that evaluate the effect of beta-blockers on the
progression of CKD and proteinuria are limited.
These agents can be considered as second- or thirdline therapy if the patient has a compelling indication
for a beta-blocker such as coronary artery disease or
chronic heart failure.
Blood pressure targets and treatment
recommendations in CKD
Optimal use of home blood pressure
measurements