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Intact PTH (1–84 PTH) is the 84-amino acid biologically active form of this

hormone. It is metabolized into smaller, less-active fragments (e.g., 7–84 PTH) with

activity that is not well characterized. These fragments are cleared from the

circulation by the kidney and may accumulate in patients with CKD. Assays used for

iPTH measure the intact structure as well as the biologically active and inactive PTH

fragments. Thus, proposed ranges for iPTH in current guidelines are based on these

assays. Assays that measure only the biologically active form (1–84 biPTH) have

become available (third-generation assays). When iPTH is measured using both

methods, there is roughly a 2:1 ratio between the second- and third-generation assay

results. An iPTH of 150 pg/mL would correspond to a biPTH 75 pg/mL.

150 These

assays correlate very well and the third-generation assay offers no advantage over

the widely used second-generation assay. Clearly, the clinician must know which

assay has been used to appropriately interpret the results, establish the desired PTH

range, and correctly adjust therapy.

The KDIGO guidelines vary as they recommend iPTH levels to be maintained

within the normal limits in CKD 3 and 4. However, the CKD 5D iPTH target range is

2 to 9 times the upper normal limits, approximately 150 to 600 pg/mL.

Dose adjustments of calcitriol are generally made in 0.5- to 1.0-mcg increments

every 2 to 4 weeks in the early stages of therapy until iPTH and serum calcium are

maintained at target levels. If hypercalcemia develops, the decision to withhold

therapy or to switch to a less hypercalcemic VDRA must be made. Serum iPTH

should be monitored every 3 to 6 months, and adjustments of calcitriol doses made to

maintain the goal iPTH and to prevent hypercalcemia and hyperphosphatemia.

Paricalcitol

The unique interactions of vitamin D with the VDR led to the development of

designer vitamin D analogs, which vary in their affinity for the VDR. In the case of

treatment for SHPT, some were developed to retain the suppressive effect on PTH

release while decreasing the potential for hypercalcemia relative to calcitriol.

Currently approved agents for managing SHPT in the United States are paricalcitol

(Zemplar), also referred to as 19-nor-1,25-dihydroxyvitamin D2

, and doxercalciferol

(Hectorol), or 1-α-hydroxyvitamin D2

. Doxercalciferol requires conversion to the

active form (1-α-,25-dihydroxyvitamin D2

) by the liver.

In patients with SHPT, paricalcitol significantly decreases iPTH without

significantly increasing calcium or phosphorus. Paricalcitol is approximately 10-fold

less hypercalcemic and hyperphosphatemic than calcitriol.

151,152 The initial dose of IV

paricalcitol is 0.04 mcg/kg to 0.1 mcg/kg (2.8–7 mcg) administered with each

dialysis session or every other day.

153 Oral paricalcitol capsules are available in

three strengths (1, 2, and 4 mcg) administered daily or 3 times weekly. The starting

dose should be 1 mcg daily or 2 mcg 3 times weekly if the baseline iPTH level is

500 pg/mL or less, and 2 mcg daily or 4 mcg 3 times weekly if the iPTH is greater

than 500 pg/mL. Some data have also suggested paricalcitol dosing based on initial

PTH levels (paricalcitol dose = PTH/80) rather than weight as a reasonable dosing

strategy.

153 Doses can be titrated every 2 to 4 weeks based on iPTH values.

The recommended conversion ratio for calcitriol to paricalcitol is 1:4 (i.e., for

every 1 mcg of calcitriol, 4 mcg of paricalcitol should be administered). This

information is based on similar efficacy observed when patients treated for SHPT

with calcitriol were switched to paricalcitol using this dosing strategy.

151,152 A lower

ratio of 1:3 also has been proposed in patients resistant to therapy with calcitriol.

Doxercalciferol

Doxercalciferol, another vitamin D analog, is an alternative to calcitriol and has been

studied in patients with CKD 5D. Doxercalciferol has similar effects on PTH as the

other vitamin D analogs; however, it increases phosphorus and calcium to a greater

degree than paricalcitol.

154 Doxercalciferol is available as a capsule and IV

injection. The doses were 4 mcg IV or 10 mcg orally 3 times a week with HD. Oral

and IV therapy are both effective in reducing iPTH levels in patients with SHPT;

however, some evidence indicated that intermittent IV therapy may result in less

hypercalcemia and hyperphosphatemia than oral intermittent therapy.

155 The

recommended starting dose of doxercalciferol for patients on dialysis is 4 mcg IV or

10 mcg orally administered 3 times a week with dosing titration based on changes in

iPTH.

156,157

Vitamin D analogs offer an alternative for patients in whom persistent

hypercalcemia develops with calcitriol therapy. Use of these agents is increasing in

clinical practice because of the concerns of hypercalcemia and its adverse

consequences. Repeated observational reports indicate lower overall and

cardiovascular-related mortality rates with activated vitamin D therapy, regardless

of the agent received, than in those not receiving vitamin D therapy.

158 Two trials

also examined survival advantages among the different forms of vitamin D in patients

on HD. One report indicated that receiving paricalcitol for 36 months conferred a

survival advantage starting at 12 months from initiation of therapy and increased with

time compared with those receiving calcitriol. Another study reported that patients

taking either paricalcitol or doxercalciferol had a significantly lower mortality rate

than patients receiving calcitriol, although when adjusted for laboratory values and

clinic standardized mortality, no difference was found between the products.

158

Possible biologic reasons for vitamin D improving outcomes include its role in

downregulating the RAAS and immunomodulatory properties. A prospective trial

would be required to confirm a survival advantage associated with vitamin D

therapy.

CALCIMIMETICS

Calcimimetic agents increase the sensitivity of the calcium-sensing receptors (CaSR)

to extracellular calcium ions and inhibit the release of PTH, lowering PTH levels

within hours after administration. The discovery of extracellular CaSR prompted

research with calcimimetic agents that allosterically modulate CaSR. CaSR are

located in the parathyroid gland, thyroid, nephron, brain, intestine, bone, lung, and

other tissues.

159 The calcimimetic cinacalcet is the first agent in this class to be

approved by the FDA to treat SHPT in ESRD.

160 Cinacalcet is an effective agent at

reducing and sustaining iPTH within target concentrations in HD patients.

161

Cinacalcet offers an additional choice of agent to lower PTH when vitamin D cannot

be increased because of elevated calcium or phosphorus. The EVOLVE trial was a

randomized clinical trial comparing cinacalcet to placebo in 3,883 dialysis patients

with

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a primary outcome of death, cardiovascular events, or hospitalizations. Patients were

eligible to receive phosphate binders or vitamin D analogs in either arm. There was

7% nonsignificant reduction in primary end points in the cinacalcet group.

162

However, issues plagued the large trial as several patients in the placebo arm

actually received cinacalcet therapy. The survival benefits of cinacalcet remained

undetermined. Cinacalcet is not FDA approved for use in CKD patients not receiving

dialysis because it is associated with frequent hypocalcemic episodes.

163

Appropriate treatment for W.K. should be based on assessment of her serum

calcium, phosphorus, and PTH values. She currently has an elevated PTH,

phosphorus, and calcium; therefore, cinacalcet should be started in conjunction with

her dietary phosphorus restriction, phosphate binder regimen, and vitamin D therapy.

Cinacalcet should be initiated at a dose of 30 mg daily, with dosage titrations

occurring every 2 to 4 weeks to 60, 90, 120, or a maximum of 180 mg daily to

achieve target iPTH levels. Serum calcium and phosphorous levels should be drawn

within 1 week after initiation or dosage increase, and plasma PTH levels drawn

within 4 weeks after initiation of therapy or dosage adjustment. Nausea and vomiting

are the most common adverse events associated with cinacalcet. Nausea is twice as

likely to occur at any dose, while vomiting is more frequent at higher doses.

162

In

phase III trials, 66% of patients receiving cinacalcet experienced at least one episode

of hypocalcemia (serum calcium <8.4 mg/dL), although less than 1% of patients

discontinued treatment.

164 The high incidence of hypocalcemia is not solely caused by

lowered PTH activity but is also attributed to the mechanism of action of cinacalcet.

It is thought that activation of CaSR in bone, intestine, and other tissues may

contribute to hypocalcemia. Most episodes of hypocalcemia occur during the

initiation of cinacalcet therapy, and slowly titrating the dose reduces the risk.

Seizures caused by hypocalcemia have been reported. Vitamin D or calcium-based

phosphate binders can be used to increase serum calcium levels between 7.5 and 8.4

mg/dL. If serum calcium falls below 7.5 mg/dL and is associated with symptoms of

hypocalcemia and vitamin D cannot be increased further, cinacalcet should be

withheld until serum calcium normalizes or the patient is asymptomatic. Cinacalcet is

a strong in vitro inhibitor of cytochrome P-450 isoenzyme CYP2D6; therefore, dose

adjustments of concomitant medications that are predominantly metabolized by

CYP2D6 may be required. Cinacalcet is also a substrate of CYP3A4, and

ketoconazole, a potent inhibitor of CYP3A4, has been shown to increase the area

under the curve of cinacalcet 2.3 times. Thus, other inhibitors of the CYP3A4

isoenzyme should be used with caution in patients receiving cinacalcet.

160

PARATHYROIDECTOMY

The parathyroid glands enlarge as a compensatory response to disturbances of

phosphorus, calcium, and calcitriol metabolism in patients with CKD. Timely

administration of vitamin D therapy to prevent parathyroid hyperplasia is crucial as

treatment with vitamin D cannot adequately reverse established hyperplasia. A

parathyroidectomy is often reserved for patients with severe hyperparathyroidism

with PTH values greater than 1,000 pg/mL, concomitant hypercalcemia, and failure

to respond to pharmacologic therapy.

91 Parathyroidectomy can be subtotal, total, or

total with autotransplantation. One of the major complications of parathyroidectomy

is the early development of postsurgical hypocalcemia.

165 Clinical symptoms of

hypocalcemia include muscle irritability, fatigue, depression, and memory loss.

Patients should be monitored closely after parathyroidectomy, and all patients with

signs or symptoms of hypocalcemia should be treated with calcium supplementation

(see Chapter 27, Fluid and Electrolyte Disorders). In patients who have had subtotal

parathyroidectomy, the remaining parathyroid tissues will start functioning

adequately, so the acute hypocalcemia is transient, lasting only a few days.

Hypocalcemia is permanent in total parathyroidectomy and requires long-term

treatment with calcitriol and oral calcium supplements (1–1.5 g/day of elemental

calcium). Studies investigating SHPT management with cinacalcet report reduced

rates of parathyroidectomy surgeries.

162,166

OTHER COMPLICATIONS OF CKD

Endocrine Abnormalities Caused by Uremia

CASE 28-3, QUESTION 3: Does W.K.’s hypothyroidism have any relationship to her CKD? What other

endocrine abnormalities are associated with uremia?

Disturbances in thyroid function are frequently encountered in patients with CKD

because the kidney is involved in all aspects of peripheral thyroid hormone

metabolism. Common laboratory abnormalities include reduced serum concentrations

of total thyroxine (T4

) and 3,5,3′-triiodothyronine (T3

) and a low free thyroxine index

(FTI). The thyroid-stimulating hormone (TSH) concentration is usually normal, but

peripheral conversion of T4

to T3

is reduced in uremic patients.

167 Despite these

abnormalities, clinical hypothyroidism does not occur solely as a result of kidney

disease, probably because the amount of free (unbound to protein) thyroid hormone in

serum remains normal. Hypothyroidism in patients with kidney failure should be

confirmed by the presence of an elevated serum TSH concentration and a low serum

concentration of free T4

.

Other endocrine abnormalities that have been observed in patients with CKD

include gonadal dysfunction leading to impotence, diminished testicular size,

menstrual abnormalities, and cessation of ovulation.

168 Decreased libido and

infertility occur in both sexes. Uremic women of childbearing age should be

counseled on the risk of becoming pregnant because of the multiple complications of

pregnancy in ESRD, including high termination rates.

169

Altered Glucose and Insulin Metabolism

CASE 28-3, QUESTION 4: Other than the obvious effect of W.K.’s diabetes mellitus on blood glucose, are

there any effects of kidney disease itself on glucose metabolism?

Uremia often is associated with glucose intolerance early in the course of kidney

disease in nondiabetic patients. Specifically, patients with CKD often exhibit an

abnormal response to an oral glucose challenge and have sustained

hyperinsulinemia.

170,171 The fasting blood glucose is typically within normal limits.

Diminished tissue sensitivity to the action of insulin is also observed. Inflammation

and oxidative stress are likely contributors predisposing CKD patients to insulin

resistance.

172 Most nondiabetic patients with kidney disease do not require therapy

for hyperglycemia, and dialysis can correct these abnormalities in glucose

metabolism.

Patients with diabetes mellitus and advanced kidney disease may experience

improved glucose control and decreased insulin requirements. This is because the

kidney is responsible for a substantial amount of daily insulin degradation and, as the

disease progresses, less insulin is cleared and its metabolic half-life is increased. A

decreased clearance of insulin by muscle tissue also can occur in patients with

uremia.

173 Thus, in diabetic patients with progressive kidney disease, blood glucose

concentrations

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should be monitored and insulin doses adjusted to avoid hypoglycemia. W.K. has

CKD 5D and is receiving her insulin in the peritoneal dialysate solution.

Hyperglycemia is also a concern in W.K. because the glucose present in her

continuous ambulatory peritoneal dialysis (CAPD) fluid to promote fluid removal

will be absorbed systemically. Insulin dosage adjustments should be made on the

basis of repeated home blood glucose measurements, changes in the CAPD

prescription, and glycosylated hemoglobin determinations.

Gastrointestinal Complications

CASE 28-3, QUESTION 5: One month before her current clinic visit, W.K. complained of nausea and

vomiting of partially digested food. Metoclopramide (Reglan) was begun at that time. Could W.K.’s nausea and

vomiting have been caused by her kidney failure? Was the appropriate therapy selected?

GI abnormalities are extremely common in patients with CKD and include

anorexia, nausea, vomiting, hiccups, abdominal pain, GI bleeding, diarrhea, and

constipation. Diminished gastric motility can occur from uremia; however, this

problem may improve with adequate HD. Dyspeptic complaints and gastroparesis

may be more prevalent in the PD population than in the HD population and in the

earlier stages of CKD.

174 W.K. has diabetes and diabetic neuropathy, which also

contributes to the delayed gastric emptying (diabetic gastroparesis) and retention of

food in the upper intestinal tract. This frequently causes distension, nausea, and

vomiting. Metoclopramide is recommended to relieve these symptoms, although the

risk for extrapyramidal side effects should be considered. A lower dose of 5 mg

before meals may be warranted for W.K.

Severe uremia also causes nausea and vomiting, and these can be initial presenting

symptoms of kidney failure. At this stage of clinical presentation, dialysis is the

preferred therapy. Drug-induced nausea and vomiting always should be considered

because patients with CKD often take multiple drugs and are at risk for drug toxicity

because of diminished kidney function (e.g., digitalis intoxication).

BLEEDING

CASE 28-3, QUESTION 6: During her clinic visit, W.K. reports that her bowel movements have become

black and tarry in appearance. A rectal examination reveals guaiac-positive stools. Is GI bleeding related to

kidney failure?

W.K. should be evaluated for peptic ulcer disease and lower GI bleeding. Uremic

patients are at risk for bleeding from mucosal surfaces such as the stomach.

Angiodysplasia of the stomach and duodenum, as well as erosive esophagitis, are the

most common causes of bleeding in patients with CKD.

175 Treatment of upper GI

bleeding in uremic patients usually consists of cautious use of H2

-receptor

antagonists, which should be given in reduced doses according to the degree of

kidney function. Proton-pump inhibitors are primarily eliminated by nonkidney routes

and can be administered at standard doses (see Chapter 23, Upper Gastrointestinal

Disorders).

Dermatologic Complications

Several dermal abnormalities have been observed in patients with CKD, including

hyperpigmentation, abnormal perspiration, skin dryness, and persistent pruritus. Of

these, uremic pruritus can be the most bothersome for the patient and may lead to

repeated scratching and skin excoriation. Hyperparathyroidism, hypervitaminosis A,

and dermal mast cell proliferation with subsequent histamine release have been

suggested as causes of pruritus.

176

Treatment of pruritus often is a frustrating experience for the patient and clinician.

Although many therapies have been advocated, few have provided sustained benefit.

A trial-and-error approach is recommended. Efficient dialysis therapy relieves

pruritus in some patients and pharmacologic therapy may be avoided. When

necessary, initial pharmacologic treatment usually consists of oral antihistamines

(e.g., hydroxyzine). Topical emollients or topical steroids may provide benefit if

antihistamine therapy is not completely successful. If pruritus is still present, other

treatment options can be tried. These include cholestyramine, ultraviolet B

phototherapy, and oral administration of activated charcoal. Control of calcium,

phosphorus, and PTH concentrations is also advocated to reduce pruritus in patients

with CKD.

176

GLOMERULAR DISEASE

Glomerular diseases lead to many complications that result from disruption of normal

glomerular structure and function. Several clinical syndromes of glomerular disease

exist; however, GN, characterized as proliferation and inflammation of the

glomerulus, is observed most frequently. According to the most recent USRDS

report, GN as a broad category remains the third leading cause of ESRD in the

United States.

3

In developing countries, ESRD caused by GN is more common as a

result of various infectious processes causing kidney failure.

Nephrotic Syndrome

Nephrotic syndrome is characterized by proteinuria greater than 3.5 g/day,

hypoalbuminemia, edema, and hyperlipidemia. In more severe conditions,

hypercoagulable conditions are increased from a loss of hemostasis control proteins,

including antithrombin III, protein S, and protein C. This syndrome can occur with or

without a change in GFR. Nephrotic syndrome may be caused by a primary disease,

such as membranous glomerulopathy, which is characterized by deposition of

immune complexes, or other systemic diseases including diabetic glomerulosclerosis

and amyloidosis. Elevated serum cholesterol and triglycerides are observed in

patients with this degree of proteinuria (>3.5 g/day). This hyperlipidemic condition

also predisposes patients with nephrotic syndrome to accelerated atherosclerosis.

Hyperlipidemia itself can also contribute to progression of kidney disease. Because

nephrotic syndrome is associated with numerous causes, further evaluation of the

patient for systemic causes is required to determine the course of therapy and

prognosis.

Chronic Glomerulopathies

GN can occur as a primary disease that is idiopathic in origin (e.g., focal segmental

glomerulosclerosis [FSGS]) or as a secondary manifestation of other systemic

disease (e.g., lupus nephritis [LN], Wegener granulomatosis). Kidney biopsy is often

required for definitive diagnosis. Glomerular lesions associated with

glomerulopathies are characterized as diffuse, focal, or segmental, depending on the

extent of involvement of individual glomeruli. Pathologic changes are characterized

as proliferative, membranous, and sclerotic based on the pattern observed.

Proliferative changes usually involve an overgrowth of the epithelium or mesangium,

whereas membranous changes are typically described as a thickening of the

glomerular basement membrane. Signs and symptoms of GN include hematuria,

proteinuria, and decreased kidney function. An autoimmune reaction is the

predominant pathogenic process leading to most forms of primary and secondary GN.

Although

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