Marshall L. Stoller, Maxwell V. Meng-Urinary Stone Disease

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Chapter 10 / Modulators of Crystallization 215

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Chapter 11 / Hormonal Influences on Nephrolithiasis 221

221

From: Current Clinical Urology, Urinary Stone Disease:

A Practical Guide to Medical and Surgical Management

Edited by: M. L. Stoller and M. V. Meng © Humana Press Inc., Totowa, NJ

Hormonal Influences on Nephrolithiasis

Colonel Noah S. Schenkman, MD

and Major C. Gerry Henderson, MD

CONTENTS

INTRODUCTION

PARATHYROID HORMONE

VITAMIN D

ALCITONIN

SEX HORMONAL INFLUENCES

OTHER HORMONAL INFLUENCES

CONCLUSION

REFERENCES

Key Words: Nephrolithiasis; hormone; parathyroid; vitamin D.

INTRODUCTION

Urinary stone disease is a multifactorial disorder that is influenced by both intrinsic

and environmental factors. Diet, climate, genetics, and metabolic processes may be

involved in stone formation. Hormonal influences on stone disease have long been

acknowledged and include disorders of calcium homeostasis, sex-related differences, and

imbalances of other hormones that play a secondary role in calcium balance. Although the

pathophysiologic mechanisms of some disorders, such as hyperparathyroidism, have

been elucidated, the actions of other hormones on urolithiasis remain elusive.

PARATHYROID HORMONE

Parathyroid hormone (PTH) is an 84-amino acid single-chain polypeptide produced

in the chief cells of the parathyroid glands. The N-terminal fragment, containing residues

1–34, is the biologically active component. PTH regulates serum calcium in three target

organs: the kidney, bone, and indirectly, the intestinal mucosa. The most potent stimulus

for PTH secretion is decreased serum calcium, especially the ionized fraction (1).

222 Schenkman and Henderson

In the kidney, PTH has three major effects: (1) stimulation of 1 α-hydroxylase in

mitochondria of the proximal convoluted renal tubule that converts 25 hydroxyvitamin

to 1,25 dihydroxyvitamin D

[1,25 (OH)

], (2) promotion of renal calcium reab-

sorption in the thick ascending loop of Henle, and (3) suppression of renal tubular

reabsorption of inorganic phosphate in the proximal tubule (1,2). The actions of PTH in

the kidney are mediated by stimulating renal adenylate cyclase, leading to increased

urinary cyclic adenosine monophosphate (cAMP). In addition, PTH decreases the reab-

sorption of bicarbonate in the kidney, which leads to a hyperchloremic acidosis. This

acidosis aids in bone demineralization and decreases calcium binding to albumin, acutely

increasing the serum ionized calcium concentration. In bone, PTH stimulates osteoclasts

to breakdown apatite, releasing calcium and phosphorus into serum (Fig. 1).

Low serum calcium stimulates PTH secretion. PTH secretion is indirectly stimu-

lated by increased serum phosphate levels, which decrease serum calcium. Hypo-

magnesemia stimulates PTH release; however severe magnesium depletion will

decrease PTH because magnesium is necessary for parathyroid function. PTH is nor-

mally inhibited by increased serum calcium, elevated 1,25 (OH)

, and hypermag-

nesemia. The appropriate physiologic controls break down in primary and secondary

hyperparathyroidism.

Hyperparathyroidism

Primary hyperparathyroidism (1HPT) is the most common endocrine disorder caus-

ing hypercalcemia. 1HPT usually results from a single parathyroid adenoma in 80% of

patients. Fifteen percent of patients have hyperplasia; 5% have multiple adenomas; less

than 0.5% will have cancer. Two to three percent of all calcium stone formers have 1HPT

(3–5)with some sources noting rates as high as 8% (3–6). 1HPT is two to four times more

common in females than males, and patients usually present after the age of 50 (7).

Fig. 1. Hormonal regulation of calcium balance. Parathyroid hormone (PTH), calcitonin, and

other hormones regulate plasma levels of calcium by controlling GI absorption, renal excretion,

and bone calcium flux.

Chapter 11 / Hormonal Influences on Nephrolithiasis 223

Most cases of hyperparathyroidism are sporadic; however the disorder can occur as part

of the autosomal dominant multiple endocrine neoplasia (MEN) syndromes. MEN-1

(Wermer’s syndrome) consists of tumors of the parathyroid, pancreatic islet cells, and

the anterior pituitary. The genetic defect is at 11q13 (8). HPT is present in 95% of MEN-

1 patients and 90% of these patients present with hypercalcemia. MEN-2 (Sipple’s

syndrome) consists of tumors of the parathyroid glands and is associated with medullary

thyroid carcinoma and pheochromocytomas. The genetic defect has been mapped to

10cen-10q11.2 (9).

The mechanism for the elevated PTH in hyperparathyroidism is not clear. There

appears to be an altered set point for the response to ionized calcium; a higher level of

ionized calcium is required to turn off PTH production (10,11). An absolute increase in

the number of cells with a normal or near normal set point may cause excess production

of PTH. This mechanism may be responsible for the changes seen in parathyroid hyper-

plasia (12). In parathyroid adenomas, both mechanisms seem to be at work. In as many

as 20% of parathyroid adenomas, genetically controlled clonal expansions of chief cells

occur because of rearrangement of the PRAD1/cyclin D1 oncogene (12–15).

Hypercalcemia is responsible for most of the clinical sequelae of the disease (Table 1).

The hypercalcemia results from increased mobilization of calcium from bone, increased

calcium absorption in the gut [from PTH-stimulated 1,25 (OH)

production], and

Table 1

Clinical Features of Hypercalcemia

Neurologic and psychiatric

• Lethargy, drowsiness

• Confusion, disorientation

• Disturbed sleep, nightmares

• Irritability, depression

• Hypotonia, decreased deep tendon reflexes

• Stupor, coma

Gastrointestinal

• Anorexia, vomiting

• Constipation

• Peptic ulceration

• Acute pancreatitis

Cardiovascular

• Arrhythmias

• Synergism with digoxin

• Hypertension

Renal

• Polyuria, polydipsia

• Hypercalciuria

• Nephrocalcinosis

• Impaired glomerular filtration

224 Schenkman and Henderson

increased renal tubular reabsorption. In addition to hypercalcemia, 1HPT causes

hypercalciuria, hypophosphatemia, bone disease, neuromuscular disease, peptic ulcer

disease, pancreatitis and soft tissue calcifications (7) (Fig. 2).

There are many renal manifestations of 1HPT, including hypercalciuria, hyperphos-

phaturia, nephrolithiasis, nephrocalcinosis, hyperchloremic acidosis, hypertension, and

distal renal tubular acidosis (16). The hypercalcemia leads to increased filtered load

of calcium, which causes hypercalciuria despite the seemingly paradoxical effect of

increased reabsorption of calcium in the proximal tubules (7). Stones are a result of

hypercalciuria. Earlier series reported the incidence of stone disease in excess of 50%,

but improved diagnostic schemes and earlier detection of disease have decreased the rate

of renal calculi to 20% (16). Patients may have calcium oxalate kidney stones or cal-

cium phosphate stones caused by alkaline urine and increased phosphaturia. In addition,

increased urinary calcium and phosphate levels lead to precipitation of calcium phos-

phate salts in the soft tissues of the kidney which manifests as nephrocalcinosis. Med-

ullary nephrocalcinosis may be present; occasionally cortical areas may be involved as

well (16).

In addition to causing nephrolithiasis, 1HPT can cause chronic renal failure (17). The

long-term effects on the kidneys may be insidious. First, loss of normal medullary

concentrating ability occurs followed by impairment of glomerular filtration rate (18).

Interstitial renal disease may cause urinary frequency, nocturia and mild dehydration

impacting on the patient’s quality of life.

Concomitant with the increased urinary excretion of calcium, the patient has increased

intestinal absorption driven by increased serum levels of 1,25 (OH)

. Studies have

shown patients with hyperparathytroidism and stones have serum levels of 1,25 (OH)

that are no different from patients with hyperparathyroidism and no stones (19). Hypo-

phosphatemia secondary to hyperphosphaturia provides another stimulus for 1,25 (OH)

production. The elevated 1,25 (OH)

caused by the elevated PTH also leads to increased

intestinal absorption of calcium further increasing calcium serum concentration (7).

Fig. 2. Mnemonic used for categorizing the signs and symptoms of hyperparathyroidism.

Chapter 11 / Hormonal Influences on Nephrolithiasis 225

Diagnosis of 1HPT is made by finding an elevated PTH in the setting of serum

calcium, greater than 11.5 ng/dL (18). Often the serum calcium may be high normal or

minimally elevated in asymptomatic patients with mild disease (18,13). Detection of

PTH in serum was initially performed with cross-reactive antibodies to bovine PTH

recognizing the carboxy-terminal region of PTH. The next generation assays were

antibodies to the amino-terminal and mid region of the hormone (20,21). These assays

were followed by measurements of intact hormone by double antibodies to both ends of

PTH (22). Currently, PTH is measured by immunoradiometric and/or immunochem-

iluminometric assays providing greater specificity and sensitivity (18,13).

The cure for primary hyperparathyroidism is parathyroidectomy; however, it is not

clear that all patients need this operation. Complications from the operation may include

hypoparathyroidism and recurrent laryngeal nerve injury. Injury to this nerve leads to

vocal cord paralysis, resulting in hoarseness, or if bilateral, respiratory compromise.

Identification of patients who will benefit from parathyroidectomy can be challenging

(18). Most patients with hyperparathyroidism have a single adenoma, are female and

over 50 yr of age. Generally, hyperparathyroidism increases with age as do other

comorbidities. The factors of age and comorbidities make some patients poor operative

candidates. Risks and benefits must be carefully weighed as the sequelae of hypercalce-

mia may be disabling or life-threatening. High serum calcium causes neuromuscular

irritability. This may result in fatigue, lethargy, depression, mental confusion, or even

coma. Cardiac effects of high calcium levels include arrhythmias and cardiac arrest.

Patients with hypercalcemia can have hypertension, peptic ulcer disease, acute pancre-

atitis, hypotonia, polyuria, and polydipsia (ref. 23; Table 1).

A consensus development conference in 1991 established guidelines for surgical

intervention (24):

• Markedly elevated serum calcium.

• History of an episode of life-threatening hypercalcemia.

• Reduced creatinine clearance.

• Presence of kidney stone(s) detected by abdominal radiograph.

• Markedly elevated 24-h urinary calcium.

• Substantially reduced bone mass as determined by direct measurement.

Although 50% of the patients with 1HPT will meet these criteria for surgery, patients

with nephrolithiasis should undergo parathyroidectomy. For other patients, Rodman and

Mahler state, “because of the subtle ongoing effects of disordered calcium metabolism

that are hard to measure, there must be a reason not to operate” (18).

The experience of the surgeon may affect his willingness to operate. The learning

curve is steep; 15 or more cases per year are needed, according to Sosa et al in their survey

of parathyroid surgeons. Surgeons not performing the operation regularly should be

wary of anatomic variations in the neck (18).

Preoperative localization of the adenoma may be helpful. In 1991 the Consensus

Development Conference concluded that preoperative imaging was not necessary

because of low yield from existing technology (24). During that time, 60% positive

results and 15% false positive results were achieved with available imaging techniques.

Since that time imaging techniques have improved. Nuclear scans, including techne-

tium–99m sestamibi and technetium tetrofosmin, have greater than 95% accuracy (18,

25–28). In centers where a high volume of parathyroid imaging is performed, standard

computed tomography (CT) scan and ultrasound are reported to have 95% accuracy (18).