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121

Because H.B. is just beginning dialysis therapy, it is difficult to assess the degree

to which volume removal will ultimately affect his BP. To control BP related to

volume changes, dialysis therapy should be adjusted as needed to achieve H.B.’s dry

weight, the postdialysis weight at which symptoms of hypervolemia and hypovolemia

are absent (i.e., normovolemia and free from edema). H.B. has had recent findings

consistent with worsening volume status (shortness of breath, weight gain) that

should be considered when modifying his dialysis prescription; further workup is

needed to determine whether H.B. has systolic or diastolic heart failure. It is also

important to counsel H.B. on the importance of salt and fluid intake restriction

between HD sessions to minimize weight gain, volume expansion, and hypertension.

Restriction of salt

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intake to less than 2.4 g/day and fluid to 1 L/day is appropriate and will require

regular follow-up by a dietitian.

ANTIHYPERTENSIVE THERAPY

Currently, there are no published guidelines for the management of hypertension in

patients receiving hemodialysis. Although there are no published guidelines, control

and management of hypertension is important. Antihypertensive therapy should be

used in conjunction with dialysis therapy in H.B. to a target BP. In the absence of

published guidelines targeting a BP of <150/90 mm Hg before HD is reasonable.

For some patients, initiation of dialysis alone may achieve this goal, and

antihypertensive therapy may be withdrawn. The aim of the BP goal in patients with

CKD 5D is to minimize cardiovascular complications, but it should not increase the

risk for hypotension and its associated complications during dialysis. The choice of

an agent is based on the patient’s comorbid conditions because no single agent has a

consistently proven mortality benefit in patients on HD. The complexity of managing

hypertension in patients on HD is enhanced by the apparent U-shaped relationship

between BP and mortality.

122 A study of patients on HD found an increased risk of

cardiac-related death at a systolic BP less than 110 mm Hg and at a systolic BP

greater than 180 mm Hg.

123 Another cohort study found a systolic BP between 100

and 125 mm Hg was associated with the lowest risk of death, and systolic BP >150

mm Hg associated with increased death.

122 The mortality risk with a low pre-HD BP

may be indicative of severe cardiac disease at the initiation of HD. If patients

experience hypotensive symptoms during HD, the goal BP can be increased, but they

also should be evaluated for other cardiovascular disorders. Because the BP

between dialysis sessions varies owing to volume changes, the ideal time to measure

BP relative to dialysis (i.e., predialysis versus postdialysis) is unclear, but

predialysis BP has been favored.

Diuretics are commonly used in patients in the early stages of CKD. As discussed

previously, the effectiveness of diuretics depends on the amount of sodium delivered

to their site of action in the kidney tubule and on the patient’s kidney function. For

example, a decrease in the eGFR from 125 to 25 mL/minute/1.73 m2

, theoretically,

could result in an approximate 80% decrease in the amount of sodium filtered. Early

in the course of kidney failure, thiazides or thiazide-like diuretics are effective

antihypertensive agents. As eGFR is further reduced (eGFR <30 mL/minute/1.73 m2

),

the thiazide diuretics become less effective. Potassium-sparing diuretics are also

ineffective and may increase the risk of hyperkalemia. Loop diuretics (e.g.,

furosemide), which function more proximally, are indicated in patients with CKD 4

(eGFR 15–29 mL/minute/1.73 m2

).

124 These drugs can be effective for BP and

volume control in patients with advanced kidney disease if residual kidney function

is substantial (urine output >100 mL/day). Their effect must be frequently reevaluated

on the basis of urine output and any effect on volume control. H.B.’s urine output

should be assessed to determine the rationale for continued use of furosemide, and

the current dose should be assessed because doses higher than his current dose of 80

mg BID are often required in patients with this degree of kidney dysfunction. It is

likely that furosemide will need to be discontinued as H.B.’s residual kidney function

declines.

Given the role of the renin–angiotensin system in the development of hypertension

in patients with CKD, ACEIs are a logical choice for antihypertensive therapy.

ACEIs are effective antihypertensive agents in patients with CKD and have been

shown to reverse LVH.

125 ACEIs are underused in this population. Response must be

assessed individually to determine whether renin–angiotensin–aldosterone activity is

a predominant etiology of hypertension. Initiating therapy with low doses is prudent

to evaluate patient response and tolerance. Use of these agents in combination with

other antihypertensives is often required for adequate BP control. Most of these

agents can be administered once daily; however, because of the kidney elimination of

the parent drug or active metabolite, dosage adjustments are necessary in patients

with CKD. ACEI use should be avoided in patients undergoing dialysis with the

polyacrylonitrile (AN69) membranes. The AN69 dialyzer increases bradykinin

production, whereas ACEIs decrease the breakdown of bradykinin, predisposing

patients to systemic or immune-mediated reactions that can lead to anaphylactic

reactions.

ARBs effectively lower BP and reverse LVH in patients without kidney disease.

126

These agents offer an alternative to ACEIs in patients experiencing kinin-mediated

adverse effects; however, similar side effects have been reported with ARBs.

β-Adrenergic blockers (β-blockers) inhibit release of renin and may be useful in

hypertension associated with CKD. β-Blockers can counteract the elevated

sympathetic activity observed in dialysis patients, lower the risk of sudden cardiac

death, and improve survival in heart failure.

127 Unfortunately, they are underutilized,

and the mentioned benefits are understudied in the dialysis population.

128 Risk versus

benefit should be evaluated when β-blockade is considered in conjunction with other

comorbid conditions such as asthma, heart failure, and lipid abnormalities. Dosage

adjustment is required for the less lipophilic agents (i.e., atenolol, nadolol).

Calcium-channel blockers are effective antihypertensive agents in patients with

CKD. Because the nondihydropyridine agents (i.e., diltiazem, verapamil) have

negative chronotropic and inotropic effects, they should be used with care in patients

with heart disease. Generally, dosage adjustment is not required in patients with

kidney disease.

Other agents used to treat hypertension in the CKD population include centrally

acting agents (e.g., clonidine, methyldopa), vasodilators (e.g., minoxidil,

hydralazine), and α1

-adrenergic blockers (prazosin, terazosin, doxazosin). However,

these agents are generally reserved as last-line therapies.

H.B. is currently taking the β-blocker metoprolol and the loop diuretic furosemide.

Metoprolol is a β-blocker considered to be removed by dialysis and should be

monitored closely for H.B. clinical response to the therapy while starting dialysis. It

is likely that his diuretic will need to be discontinued as his residual kidney function

decreases and response to therapy is inadequate. If changes imposed in H.B.’s HD

prescription are able to improve volume control and achieve his dry weight but do

not reduce his BP, another antihypertensive regimen should be selected. A

reasonable antihypertensive regimen would include an ACEI (e.g., ramipril). The

selection will depend substantially on follow-up results of his cardiac disease, BP

control with HD, and the development of adverse effects (see Chapter 9, Essential

Hypertension, and Chapter 14, Heart Failure).

Dyslipidemia

CASE 28-2, QUESTION 3: How should H.B.’s lipid abnormalities be treated?

H.B. has elevated serum cholesterol and triglyceride concentrations, a common

finding in patients with CKD. Dyslipidemia and increased oxidative stress contribute

to premature atherogenesis in these patients. Several atherogenic factors in patients

with CKD have been postulated, including arterial wall injury, platelet activation and

adherence, smooth muscle cell proliferation, and intraarterial accumulation of

cholesterol. Lowering of serum lipids has not been shown to improve morbidity and

mortality in hemodialysis patients. Furthermore, current KDIGO Guidelines for Lipid

Management in CKD do not recommend using

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cholesterol values to determine who to treat or as treatment targets. Currently,

H.B. is not receiving a statin which has not demonstrated the ability to reduce

mortality or morbidity in dialysis. If concern with treating H.B.’s dyslipidemia

persists, a moderate-intensity statin may be considered. Dietary intervention

successfully reduces triglyceride and cholesterol concentrations in patients with

CKD 5D.

MINERAL AND BONE DISORDERS

CASE 28-3

QUESTION 1: W.K. is a 24-year-old Hispanic woman who has an 18-year history of type 1 diabetes mellitus

with complications of diabetic nephropathy, retinopathy, and neuropathy. She was diagnosed with CKD 5 two

years ago. She started PD at that time. Her current medications include metoclopramide (Reglan) 10 mg TID

before meals, insulin aspart 10 units with meals, insulin glargine 25 units nightly, docusate 100 mg every day,

calcium acetate 2001 mg PO TID with meals, EPO 5,000 units IV twice weekly, iron sucrose 100 mg IV 3

times a week, paricalcitol 4 mcg IV 3 times weekly, and Nephrocaps one capsule every day. At a recent clinic

visit, findings on physical examination included a BP of 128/84 mm Hg, diabetic retinopathic changes with laser

scars bilaterally, and diminished sensation bilaterally below the knees. Her laboratory values were as follows:

Normalserum electrolytes

Random blood glucose, 250 mg/dL

BUN, 45 mg/dL

SCr, 8.9 mg/dL

Hgb, 10 g/dL

WBC count, 6,200/μL

Calcium, 10.2 mg/dL

Phosphate, 6.8 mg/dL

Intact parathyroid hormone (iPTH), 950 pg/mL

Thyroid-stimulating hormone, 5 mIU/L

Totalserum protein, 5.0 g/dL

Serum albumin, 3.1 g/dL

Uric acid, 8.9 mg/dL

Describe the etiology of W.K.’s abnormal bone, calcium, phosphorus, and parathyroid hormone (PTH)

findings.

Etiology

MND of CKD (CKD-MBD) is the term used to collectively describe the mineral

(e.g., phosphorus, calcium, PTH), bone (osteodystrophy), and soft-tissue

calcification abnormalities that develop as a complication of CKD. The older

collective term of renal osteodystrophy failed to adequately illustrate the broader

clinical complications associated with the biomarker abnormalities and calcification,

and is now only used to describe, specifically, the bone pathology.

92

Hyperphosphatemia, hypocalcemia, hyperparathyroidism, decreased production of

active vitamin D, and resistance to vitamin D therapy are all frequent problems in

CKD that can lead to the secondary complications of CKD-MBD. Although the

interrelationships among phosphorus, calcium, vitamin D, and PTH have been

reviewed extensively, f ibroblast growth factor 23 (FGF23), a phosphaturic

hormone, has added some new insight.

129

Increased dietary phosphorus intake

stimulates FGF23 secretion. FGF23 increases phosphorus excretion via the proximal

tubules, inhibits vitamin D activation, increases activated vitamin D catabolism, and

is associated with kidney disease progression.

130

At a GFR above 30 mL/minute/1.73 m2

, elevations in FGF23 and PTH maintain

normal serum phosphorus. This concept is referred to as the trade-off hypothesis,

where the ability to maintain normal phosphorus concentrations occurs at the expense

of developing secondary hyperparathyroidism (SHPT), the excessive secretion of

PTH and elevated FGF23. However, FGF23 is not currently measured in the clinical

setting. Clinically significant increases in serum phosphorus (or frank

hyperphosphatemia) typically are not seen until late stages of CKD, GFR <30

mL/minute/1.73 m2

, when compensatory mechanisms within the kidney are

compromised.

The kidney is the principal organ responsible for systemic vitamin D production,

and, as such, vitamin D metabolism is altered in the presence of uremia. Persistent

hyperphosphatemia stimulates the release of excessive FGF23, which inhibits the

normal conversion of 25-hydroxyvitamin D3

to its biologically active metabolite,

1,25-dihydroxyvitamin D3

, by the enzyme 1-α-hydroxylase (Fig. 28-2). This enzyme

is present in proximal tubular cells of the kidney and is necessary for conversion of

vitamin D to the active form. This active form of vitamin D, also known as calcitriol,

increases gut absorption of calcium and interacts with vitamin D receptors on the

parathyroid gland to suppress PTH release. As a result of decreased calcitriol

production, the absorption of dietary calcium in the gut is diminished. Decreased

suppression of PTH release by vitamin D in conjunction with hypocalcemia promotes

continued stimulus for mobilization of calcium from bone. Furthermore, uremic

patients require a higher extracellular calcium concentration to suppress secretion of

PTH. This is also described as an increase in the calcium “set point” or the

concentration of calcium required to inhibit 50% of maximal PTH secretion.

131

The chronic effects of hyperparathyroidism on the skeleton lead to bone pain,

fractures, and myopathy. In children, these effects may be particularly severe and

usually retard growth. The metabolic acidosis of kidney disease also contributes to a

negative calcium balance in the bone.

W.K.’s presentation is consistent with CKD-MBD based on the observed changes

in bone architecture and abnormalities in serum phosphorus, calcium, and PTH; all

can be attributed to her kidney disease.

Vitamin D levels (i.e., 25-hydroxyvitamin D) should be checked in CKD 3.

Insufficient (<30 ng/mL) and deficient (<15 ng/mL) vitamin D levels are prevalent in

the majority of CKD and ESRD patients. Several studies have linked depressed

vitamin D levels to increased vascular calcification, CVD, and mortality.

132

Figure 28-2 Vitamin D biotransformation.

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