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 diagnosisFigure 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 formationProteinuriaTubulo-interstitial fibrosis

Normal glomerulus

Kimmelstiel-Wilson Nodule

Diagnosis

History of Diabetes MellitusProteinuriaPresence of other diabetic complications eg retinopathyRenal Impairment in later stagesNote no haematuria – if present may require renal

biopsy

Albuminuria

Normoalbuminuria <30mg/g creatinineMicroalbuminuria 30-300 mg/g creatinineMacroalbuminuria >300 mg/g creatinine

Time Course of Type 2 Diabetic Renal Disease

Early Stage Late Stage End Stage

Microalbuminuria Proteinuria ESRD

Kidney Disease

Cardiovascular Morbidity and Mortality

The greater the proteinuria, the higher the CV risk

Proteinuria in Diabetics

Prevention & Treatment

Glycaemic controlMaintain tight glycaemic control (HbA1c < 7)

Anti-hypertensive therapyTight 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 Renin-Angiotensin 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

Nondihydropyridine

Dihydropyridine

Diuretics and Low Sodium

Intakeβ-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 intermediate-acting 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 non-dipping, 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 renin-angiotensinaldosterone system (RAAS), such as angiotensin-converting 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 third-

line 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