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.
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.
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
(Hectorol), or 1-α-hydroxyvitamin D2
. Doxercalciferol requires conversion to the
active form (1-α-,25-dihydroxyvitamin D2
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
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.
ratio of 1:3 also has been proposed in patients resistant to therapy with calcitriol.
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
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.
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
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.
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.
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
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
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.
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
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.
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.
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.
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
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.
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.
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.
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
) and 3,5,3′-triiodothyronine (T3
) and a low free thyroxine index
(FTI). The thyroid-stimulating hormone (TSH) concentration is usually normal, but
is reduced in uremic patients.
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
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.
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.
Altered Glucose and Insulin Metabolism
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
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
172 Most nondiabetic patients with kidney disease do not require therapy
for hyperglycemia, and dialysis can correct these abnormalities in glucose
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
173 Thus, in diabetic patients with progressive kidney disease, blood glucose
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 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
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).
CASE 28-3, QUESTION 6: During her clinic visit, W.K. reports that her bowel movements have become
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.
bleeding in uremic patients usually consists of cautious use of H2
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
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.
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
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
In developing countries, ESRD caused by GN is more common as a
result of various infectious processes causing kidney failure.
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
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.
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