Advances in Peritoneal Dialysis, Vol. 23, 2007

The goal of the present case report is to enhance

recognition of the incidence of tissue calcifications,

which are quite common in patients with end-stage

renal disease. We focus on pulmonary metastatic cal-

cifications and the potential progression of this con-

dition to tissue necrosis and lung cavitations in the

setting of severe electrolyte imbalance. This case

highlights the importance of early identification of

the causes and potential risk factors leading to vis-

ceral calciphylaxis.

Key words

Pulmonary calciphylaxis, metastatic pulmonary cal-

cification, high-resolution computed tomography,

HRCT, end-stage renal disease, ESRD, hemodialysis

Introduction

Ectopic pulmonary calcification is divided into two

types based on pathophysiologic and underlying his-

tologic characteristics. Dystrophic calcifications

occur when calcium salts are deposited into patho-

logically abnormal tissues. For instance, in granulo-

matous diseases, calcium salts precipitate in necrotic

tissue. On the other hand, metastatic calcification is

considered a metabolic disorder that occurs in the

setting of electrolyte imbalance and involves calcium

deposition into otherwise normal tissues. The meta-

static calcification process predominantly affects

blood vessels, periarticular soft tissues, lungs, stom-

ach, kidneys, and myocardium.

Metabolic Lung Disease:

Diffuse Metastatic

Pulmonary Calcifications

with Progression to

Calciphylaxis in End-Stage

Renal DiseaseArshan Beyzaei,1 Jean Francis,2 Herbert Knight,3 David B.

Simon,2 Frederic O. Finkelstein2

From: 1Department of Internal Medicine and Divisions of2Nephrology and 3Pulmonary Medicine, Hospital of St.

Raphael, 1450 Chapel Street, New Haven, Connecticut

06511 U.S.A.

Visceral calcification may develop silently over

many years and is often detected incidentally. Most

cases of metastatic pulmonary calcification occur in

patients with hypercalcemia, particularly those with

hyperparathyroidism secondary to chronic kidney

disease. Less common causes include primary hy-

perparathyroidism, extensive bone metastasis, hyper-

vitaminosis D, milk–alkali syndrome, and multiple

myeloma (1–3).

Multifocal patterns of pulmonary parenchymal

calcification may also be associated with infection (es-

pecially histoplasmosis and tuberculosis), silicosis,

diffuse parenchymal amyloidosis, alveolar proteinosis,

idiopathic pulmonary hemosiderosis, and alveolar

microlithiasis. It may also occur in metastatic malig-

nancies such as osteo genic sarcoma, chondrosarcoma,

and mucin-producing adenocarcinomas (3,4).

Histologically, metastatic pulmonary calcification

is an interstitial process characterized by deposition

of calcium in the elastic tissue of alveolar septa, ar-

teries, veins, bronchioles, and bronchi (3,5). As depo-

sition continues, the areas of involvement become

more fibrotic, and calcium deposition becomes more

plate-like (1).

Chest radiography is a relatively insensitive diag-

nostic tool. The most common radiologic manifesta-

tion consists of poorly defined nodular opacities (6,7).

More severe interstitial calcification can result in dense

areas of consolidation (2). Recently, high-resolution

computed tomography (HRCT), dual-energy digital

chest radiography, and isotope imaging using

hydroxymethylene diphosphonate (Tc-99m MDP)

have been used as effective tools to detect the pres-

ence of pulmonary calcifications (8,9). The most com-

mon parenchymal finding on HRCT is the presence

Beyzaei et al. 113

of centrilobular “ground glass” nodular opacities, with

numerous fluffy and poorly defined nodules measur-

ing 3 – 10 mm in diameter (2,7). Calcification, when

evident on CT, can be punctate within the nodular

opacities or ring-like, or they can involve the entire

nodule (2,3,6,7). Additionally, calcification in the ves-

sels of the chest wall is often seen on the CT scan as

well. The combination of pulmonary and vascular cal-

cification is characteristic of metastatic pulmonary

calcification (7). When the calcification pattern be-

comes confluent, it may mimic a consolidative pro-

cess and may be misdiagnosed as pulmonary edema

or pneumonia (2).

Most patients with metastatic pulmonary calcifi-

cation are asymptomatic. Pulmonary function tests are

usually normal in the early stages of the disease. With

disease progression, restrictive lung changes may de-

velop, with decrease in vital capacity and diffusion

capacity leading to hypoxemia (6).

Several types of tissue calcification have been

described from radiographic evaluation of patients

with end-stage renal disease (ESRD). Abnormal pul-

monary and cardiac calcifications have been reported

at autopsy in 40% – 80% of these patients (7,10).

Patients who have high Ca×P product have a higher

incidence of such findings. An ion product in excess

of 60 (mg/dL)2 has been associated with tissue cal-

cifications. Local and systemic changes in pH are

both responsible for inducing calcification in soft

tissues. Because of their relative alkaline environ-

ments, the lungs, kidneys, and stomach wall are pre-

disposed (11).

In lung, metastatic calcification tends to involve

mainly the upper zones. This distribution is related to

the lower partial pressure of CO2 in the upper zones

as a result of a higher ventilation–perfusion ratio and

thus a higher pH. A locally elevated pH favors the

deposition of calcium salts (6).

Calciphylaxis is a rare and life-threatening disor-

der characterized by small-vessel mural calcification

with intimal proliferation, fibrosis, and thrombosis,

resulting in ischemic necrosis of the tissue (8). It has

been viewed largely as a systemic disease involving

dermohypodermic arterioles, subcutaneous fat, or

muscles of the extremities. However calciphylaxis of

other organs has been reported occasionally in the lit-

erature. It occurs mostly in chronic kidney disease

patients with elevated Ca×P product in the setting of

secondary hyperparathyroidism (12).

The prevalence of calciphylaxis in dialysis patients

may be as high as 20% (13). Several risk factors con-

tributing to the syndrome have been identified, includ-

ing severe hyperparathyroidism, total or subtotal

parathyroidectomy, adynamic bone disease, and dia-

betes mellitus (13,14). Furthermore, local trauma, ste-

roid or warfarin use, protein C and S deficiencies, and

vitamin D excess have all been documented to con-

tribute to the development of calciphylaxis (8).

Case report

Our patient is a 22-year-old Hispanic male with ESRD

secondary to congenital dysplastic kidneys. When he

was 3 years old, an attempted kidney transplant failed

when complicated by immediate rejection. Subse-

quently, continuous ambulatory peritoneal dialysis

(CAPD) was initiated.

The patient’s medical history is also significant

for hypertension, anemia, asthma, obstructive sleep

apnea, and severe secondary hyperparathyroidism. He

underwent parathyroidectomy in 2003. After multiple

admissions for bacterial peritonitis, he was converted

to hemodialysis in December 2004. He also has dif-

fuse peritoneal calcifications with thickened calva-

rium, causing pseudotumor cerebri.

Since 2005, the patient has been suffering with nau-

sea and vomiting of unclear origin. An extensive gas-

trointestinal workup—including a gastric emptying

scan and multiple esophagogastroduodenoscopies—

failed to identify a cause of the persistent vomiting.

In 2004, patient was noted to have a normal chest

X-ray (CXR). In April 2005, the patient was admit-

ted to hospital with persistent fevers. Based on an

abnormal CXR, he underwent a chest HRCT, which

was significant for diffuse pulmonary calcifications

and renal osteodystrophy (Figure 1). At that point,

the patient’s calcium and vitamin D supplements

were discontinued. The fevers resolved, and he was

discharged home.

In August 2005, the patient was readmitted to hos-

pital with a primary diagnosis of pneumonia [CXR

showing right upper lobe (RUL) infiltrate]. He was

treated with a course of intravenous vancomycin and

piperacillin–tazobactam.

In January 2006, patient was readmitted with a

chief complaint of shortness of breath and worsening

of nausea and vomiting. Medications on admission

included sevelamer hydrochloride 800 mg 3 times

daily as a phosphate binder and metoclopramide 5 mg

114 Pulmonary Calciphylaxis in ESRD

daily. Physical exam revealed a blood pressure of 82/

50 mmHg, a heart rate of 86 bpm, and a temperature

of 98.2°F. A lung exam showed decreased breath

sounds with no evidence of wheezing. Heart was regu-

lar with no murmurs, rubs, or gallops. Livedo reticularis

and other signs of calciphylaxis were not seen. He-

matologic tests showed a white blood cell count of

12,200/µL with a differential of 73% neutrophils and

20% lymphocytes, a hemoglobin of 15.8 g/dL, a hema-

tocrit of 49%, and a platelet count of 159,000/µL. Blood

chemistry screening showed sodium, 152 mmol/L;

potassium, 3.8 mmol/L; chloride, 69 mmol/L; serum

bicarbonate, >50 mmol/L; calcium, 10.5 mg/dL; al-

bumin, 5.0 g/dL; phosphorus, 9.2 mg/dL; Ca×P prod-

uct, 96.6; and magnesium, 3.6 mg/dL. Renal function

tests showed a blood urea nitrogen of 38 mg/dL and a

serum creatinine of 10.1 mg/dL. Intact parathyroid

hormone measured during the course of that admis-

sion was 122 pg/mL (normal range: 10 – 65 pg/mL).

Liver function tests were unremarkable. Arterial blood

gas showed a pH of 7.39, a PO2

of 85 mmHg, and a

PCO2

of 59 mmHg. The CXR was significant for a

cavitary process in the RUL. Chest CT showed a large,

complexly septated cavity in the RUL, and some de-

struction of lung parenchyma in the left upper lobe

(LUL), although not as severe as that in the RUL (Fig-

ure 2).

The patient was started on broad spectrum antibi-

otics with intravenous vancomycin and piperacillin–

tazobactam for presumed necrotizing pneumonia.

FIGURE 1 Diffuse pulmonary calcifications were initially noted on this high-resolution computed tomography chest scan from April 2005.

Beyzaei et al. 115

He improved clinically and was discharged in stable

condition.

In March 2006, a repeat chest CT scan showed a

septated cavitary right apical lesion and LUL struc-

tural distortion relatively unchanged as compared with

the chest CT scan from January 2006. Subsequently,

the patient was started on 4 weeks of intravenous

levofloxacin for a presumed RUL infectious process.

FIGURE 2 A complex septated thick-walled cavitary process was seen in the area of the right upper lobe, together with less severe

destruction of lung parenchyma in the left upper lobe, in a chest computed tomography scan from January 2006.

116 Pulmonary Calciphylaxis in ESRD

A follow-up chest CT scan in May 2006 showed a

large RUL cavitary lesion similar in appearance to

that uncovered in previous studies. In addition, he had

progressive structural distortion and fibrotic changes

of the LUL. Bronchoscopy with bronchoalveolar lav-

age was performed in July 2006, and cultures of the

washing fluid for bacteria, mycobacteria, and fungi

were negative. Staining for Pneumocystis carinii pneu-

monia was also negative. Bronchoscopic examination

showed a diffuse pattern of shiny, whitish, linear im-

ages in the bronchial tree of both lungs, suggestive of

submucosal pulmonary calcification.

Discussion

Metastatic pulmonary calcification is a relatively com-

mon complication in patients with ESRD. It mani-

fests as tissue calcification without ischemic and

necrotic changes. Calciphylaxis, on the other hand, is

associated with medial and intimal calcification of

small- and medium-sized arteries, with ischemic ne-

crosis of involved tissue (8,15).

Pulmonary calciphylaxis is a rare disorder that has

been associated with lung necrosis. The diagnosis of

pulmonary calciphylaxis requires high suspicion, and

a definite diagnosis requires pathology examination

of tissues. Although no tissue biopsy has been done

in the present case, the setting of electrolyte imbal-

ance, negative culture results, and the progressive

nature of the lung lesions on serial imaging studies

are highly suggestive of lung tissue necrosis second-

ary to pulmonary calciphylaxis.

We speculate that high calcium and phosphate lev-

els and an alkaline environment exacerbated by

chronic vomiting are the main culprits in accelerating

the development of diffuse metastatic calcifications

and ultimately fulminant pulmonary calciphylaxis.

Predilection for calcification in the lung, especially

the upper lobes, and ultimate necrosis in those areas

is consistent with the relative alkaline environment in

those areas as a result of higher ventilation-to-perfu-

sion ratios and hence lower partial pressures of CO2.

Conclusions

Although patients with metastatic pulmonary calcifi-

cations are usually asymptomatic, calcium, phosphate,

and parathyroid hormone levels should be monitored,

and abnormalities should be treated to avoid progres-

sion to calciphylaxis. Few options exist for treating

calciphylaxis, and the outcome is generally poor.

Several causes have been proposed to explain the

development of calciphylaxis at the molecular level.

Uremia is a proinflammatory state in which levels of

interleukin-6 and tumor necrosis factor α are reported

to be elevated in most patients with ESRD. These

proinflammatory cytokines are known to contribute

to endothelial dysfunction and vascular calcification,

which may lead to the development of calciphylaxis

(8,16). In addition, a decrease in calcification inhibi-

tors such as osteoprotegerin has also been reported in

patients on hemodialysis, possibly contributing fur-

ther to development of calciphylaxis (8,17).

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Corresponding author:Fredric Finkelstein, MD, 136 Sherman Avenue, NewHaven, Connecticut 06511 U.S.A.E-mail:fof@comcast.net