Advances in Peritoneal , Vol. 23, 2007

Metabolic Lung Disease: Diffuse Metastatic Pulmonary with Progression to in End-Stage Arshan Beyzaei,1 Jean Francis,2 Herbert Knight,3 David B. Simon,2 Frederic O. Finkelstein2 Renal Disease

The goal of the present case report is to enhance Visceral may develop silently over recognition of the incidence of tissue calcifications, many years and is often detected incidentally. Most which are quite common in patients with end-stage cases of metastatic pulmonary calcification occur in renal disease. We focus on pulmonary metastatic cal- patients with hypercalcemia, particularly those with cifications and the potential progression of this con- secondary to chronic dition to tissue necrosis and lung cavitations in the disease. Less common causes include primary hy- setting of severe . This case perparathyroidism, extensive bone metastasis, hyper- highlights the importance of early identification of vitaminosis D, milk–alkali syndrome, and multiple the causes and potential risk factors leading to vis- myeloma (1–3). ceral calciphylaxis. Multifocal patterns of pulmonary parenchymal calcification may also be associated with infection (es- Key words pecially histoplasmosis and tuberculosis), silicosis, Pulmonary calciphylaxis, metastatic pulmonary cal- diffuse parenchymal amyloidosis, alveolar proteinosis, cification, high-resolution computed tomography, idiopathic pulmonary hemosiderosis, and alveolar HRCT, end-stage renal disease, ESRD, hemodialysis microlithiasis. It may also occur in metastatic malig- nancies such as osteo genic sarcoma, chondrosarcoma, Introduction and mucin-producing adenocarcinomas (3,4). Ectopic pulmonary calcification is divided into two Histologically, metastatic pulmonary calcification types based on pathophysiologic and underlying his- is an interstitial process characterized by deposition tologic characteristics. Dystrophic calcifications of in the elastic tissue of alveolar septa, ar- occur when calcium salts are deposited into patho- teries, veins, bronchioles, and bronchi (3,5). As depo- logically abnormal tissues. For instance, in granulo- sition continues, the areas of involvement become matous diseases, calcium salts precipitate in necrotic more fibrotic, and calcium deposition becomes more tissue. On the other hand, is plate-like (1). considered a metabolic disorder that occurs in the Chest radiography is a relatively insensitive diag- setting of electrolyte imbalance and involves calcium nostic tool. The most common radiologic manifesta- deposition into otherwise normal tissues. The meta- tion consists of poorly defined nodular opacities (6,7). static calcification process predominantly affects More severe interstitial calcification can result in dense blood vessels, periarticular soft tissues, lungs, stom- areas of consolidation (2). Recently, high-resolution ach, kidneys, and myocardium. computed tomography (HRCT), dual-energy digital chest radiography, and isotope imaging using From: 1Department of Internal Medicine and Divisions of hydroxymethylene diphosphonate (Tc-99m MDP) 2Nephrology and 3Pulmonary Medicine, Hospital of St. have been used as effective tools to detect the pres- Raphael, 1450 Chapel Street, New Haven, Connecticut ence of pulmonary calcifications (8,9). The most com- 06511 U.S.A. mon parenchymal finding on HRCT is the presence Beyzaei et al. 113 of centrilobular “ground glass” nodular opacities, with The prevalence of calciphylaxis in dialysis patients numerous fluffy and poorly defined nodules measur- may be as high as 20% (13). Several risk factors con- ing 3 – 10 mm in diameter (2,7). Calcification, when tributing to the syndrome have been identified, includ- evident on CT, can be punctate within the nodular ing severe hyperparathyroidism, total or subtotal opacities or ring-like, or they can involve the entire , adynamic bone disease, and dia- nodule (2,3,6,7). Additionally, calcification in the ves- betes mellitus (13,14). Furthermore, local trauma, ste- sels of the chest wall is often seen on the CT scan as roid or use, protein C and S deficiencies, and well. The combination of pulmonary and vascular cal- excess have all been documented to con- cification is characteristic of metastatic pulmonary tribute to the development of calciphylaxis (8). calcification (7). When the calcification pattern be- comes confluent, it may mimic a consolidative pro- Case report cess and may be misdiagnosed as pulmonary edema Our patient is a 22-year-old Hispanic male with ESRD or pneumonia (2). secondary to congenital dysplastic kidneys. When he Most patients with metastatic pulmonary calcifi- was 3 years old, an attempted kidney transplant failed cation are asymptomatic. Pulmonary function tests are when complicated by immediate rejection. Subse- usually normal in the early stages of the disease. With quently, continuous ambulatory peritoneal dialysis disease progression, restrictive lung changes may de- (CAPD) was initiated. velop, with decrease in vital capacity and diffusion The patient’s medical history is also significant capacity leading to hypoxemia (6). for hypertension, anemia, asthma, obstructive sleep Several types of tissue calcification have been apnea, and severe secondary hyperparathyroidism. He described from radiographic evaluation of patients underwent parathyroidectomy in 2003. After multiple with end-stage renal disease (ESRD). Abnormal pul- admissions for bacterial peritonitis, he was converted monary and cardiac calcifications have been reported to hemodialysis in December 2004. He also has dif- at autopsy in 40% – 80% of these patients (7,10). fuse peritoneal calcifications with thickened calva- Patients who have high Ca×P product have a higher rium, causing pseudotumor cerebri. incidence of such findings. An ion product in excess Since 2005, the patient has been suffering with nau- of 60 (mg/dL)2 has been associated with tissue cal- sea and vomiting of unclear origin. An extensive gas- cifications. Local and systemic changes in pH are trointestinal workup—including a gastric emptying both responsible for inducing calcification in soft scan and multiple esophagogastroduodenoscopies— tissues. Because of their relative alkaline environ- failed to identify a cause of the persistent vomiting. ments, the lungs, kidneys, and stomach wall are pre- In 2004, patient was noted to have a normal chest disposed (11). X-ray (CXR). In April 2005, the patient was admit- In lung, metastatic calcification tends to involve ted to hospital with persistent fevers. Based on an mainly the upper zones. This distribution is related to abnormal CXR, he underwent a chest HRCT, which the lower partial pressure of CO2 in the upper zones was significant for diffuse pulmonary calcifications as a result of a higher ventilation–perfusion ratio and and renal osteodystrophy (Figure 1). At that point, thus a higher pH. A locally elevated pH favors the the patient’s calcium and vitamin D supplements deposition of calcium salts (6). were discontinued. The fevers resolved, and he was Calciphylaxis is a rare and life-threatening disor- discharged home. der characterized by small-vessel mural calcification In August 2005, the patient was readmitted to hos- with intimal proliferation, fibrosis, and , pital with a primary diagnosis of pneumonia [CXR resulting in ischemic necrosis of the tissue (8). It has showing right upper lobe (RUL) infiltrate]. He was been viewed largely as a systemic disease involving treated with a course of intravenous vancomycin and dermohypodermic arterioles, subcutaneous fat, or piperacillin–tazobactam. muscles of the extremities. However calciphylaxis of In January 2006, patient was readmitted with a other organs has been reported occasionally in the lit- chief complaint of shortness of breath and worsening erature. It occurs mostly in of nausea and vomiting. Medications on admission patients with elevated Ca×P product in the setting of included sevelamer hydrochloride 800 mg 3 times secondary hyperparathyroidism (12). daily as a phosphate binder and metoclopramide 5 mg 114 Pulmonary Calciphylaxis in ESRD

FIGURE 1 Diffuse pulmonary calcifications were initially noted on this high-resolution computed tomography chest scan from April 2005. daily. Physical exam revealed a blood pressure of 82/ tests showed a blood urea nitrogen of 38 mg/dL and a 50 mmHg, a heart rate of 86 bpm, and a temperature serum creatinine of 10.1 mg/dL. Intact parathyroid of 98.2°F. A lung exam showed decreased breath hormone measured during the course of that admis- sounds with no evidence of wheezing. Heart was regu- sion was 122 pg/mL (normal range: 10 – 65 pg/mL). lar with no murmurs, rubs, or gallops. Liver function tests were unremarkable. Arterial blood and other signs of calciphylaxis were not seen. He- gas showed a pH of 7.39, a PO2 of 85 mmHg, and a matologic tests showed a white blood cell count of PCO2 of 59 mmHg. The CXR was significant for a 12,200/µL with a differential of 73% neutrophils and cavitary process in the RUL. Chest CT showed a large, 20% lymphocytes, a hemoglobin of 15.8 g/dL, a hema- complexly septated cavity in the RUL, and some de- tocrit of 49%, and a platelet count of 159,000/µL. Blood struction of lung parenchyma in the left upper lobe chemistry screening showed sodium, 152 mmol/L; (LUL), although not as severe as that in the RUL (Fig- potassium, 3.8 mmol/L; chloride, 69 mmol/L; serum ure 2). bicarbonate, >50 mmol/L; calcium, 10.5 mg/dL; al- The patient was started on broad spectrum antibi- bumin, 5.0 g/dL; phosphorus, 9.2 mg/dL; Ca×P prod- otics with intravenous vancomycin and piperacillin– uct, 96.6; and magnesium, 3.6 mg/dL. Renal function tazobactam for presumed necrotizing pneumonia. Beyzaei et al. 115

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.

He improved clinically and was discharged in stable tural distortion relatively unchanged as compared with condition. the chest CT scan from January 2006. Subsequently, In March 2006, a repeat chest CT scan showed a the patient was started on 4 weeks of intravenous septated cavitary right apical lesion and LUL struc- levofloxacin for a presumed RUL infectious process.

116 Pulmonary Calciphylaxis in ESRD

A follow-up chest CT scan in May 2006 showed a Several causes have been proposed to explain the large RUL cavitary lesion similar in appearance to development of calciphylaxis at the molecular level. that uncovered in previous studies. In addition, he had is a proinflammatory state in which levels of progressive structural distortion and fibrotic changes interleukin-6 and tumor necrosis factor α are reported of the LUL. Bronchoscopy with bronchoalveolar lav- to be elevated in most patients with ESRD. These age was performed in July 2006, and cultures of the proinflammatory cytokines are known to contribute washing fluid for bacteria, mycobacteria, and fungi to endothelial dysfunction and vascular calcification, were negative. Staining for Pneumocystis carinii pneu- which may lead to the development of calciphylaxis monia was also negative. Bronchoscopic examination (8,16). In addition, a decrease in calcification inhibi- showed a diffuse pattern of shiny, whitish, linear im- tors such as osteoprotegerin has also been reported in ages in the bronchial tree of both lungs, suggestive of patients on hemodialysis, possibly contributing fur- submucosal pulmonary calcification. ther to development of calciphylaxis (8,17).

Discussion References Metastatic pulmonary calcification is a relatively com- 1 Kobayashi T, Satoh K, Nakano S, Toyama Y, mon complication in patients with ESRD. It mani- Ohakawa M. A case of metastatic pulmonary calcifi- fests as tissue calcification without ischemic and cation after transient acute renal failure. Radiat Med necrotic changes. Calciphylaxis, on the other hand, is 2005;23:435–8. associated with medial and intimal calcification of 2 Marchiori E, Muller NL, Souza AS Jr, Escuissato DL, Gasparetto EL, de Cerqueira EM. Unusual manifesta- small- and medium-sized arteries, with ischemic ne- tions of metastatic pulmonary calcification. J Thorac crosis of involved tissue (8,15). Imaging 2005;20:66–70. Pulmonary calciphylaxis is a rare disorder that has 3 Lingam RK, Teh J, Sharma A, Friedman E. Meta- been associated with lung necrosis. The diagnosis of static pulmonary calcification in renal failure: a new pulmonary calciphylaxis requires high suspicion, and HRCT pattern. Br J Radiol 2002;75:74–7. a definite diagnosis requires pathology examination 4 Brown K, Mund DF, Aberle DR, Batra P, Young DA. In- of tissues. Although no tissue biopsy has been done trathoracic calcifications: radiographic features and dif- in the present case, the setting of electrolyte imbal- ferential diagnosis. Radiographics 1994;14:1247–61. ance, negative culture results, and the progressive 5 Greenberg S, Suster B. Metastatic pulmonary calcifi- nature of the lung lesions on serial imaging studies cation: appearance on high-resolution CT. J Comput are highly suggestive of lung tissue necrosis second- Assist Tomogr 1994;18:497–9. ary to pulmonary calciphylaxis. 6 Ullmer E, Borer H, Sandoz P, Mayr M, Dalquen P, Soler M. Diffuse pulmonary nodular infiltrates in a We speculate that high calcium and phosphate lev- renal transplant recipient. Chest 2001;120:1394–8. els and an alkaline environment exacerbated by 7 Hartman TE, Muller NL, Primack SL, et al. Meta- chronic vomiting are the main culprits in accelerating static pulmonary calcification in patients with hyper- the development of diffuse metastatic calcifications calcemia: findings on chest radiographs and CT and ultimately fulminant pulmonary calciphylaxis. scans. AJR Am J Roentgenol 1994;162:799–802. Predilection for calcification in the lung, especially 8 Li YJ, Tian YC, Chen YC, et al. Fulminant pulmo- the upper lobes, and ultimate necrosis in those areas nary calciphylaxis and metastatic calcification caus- is consistent with the relative alkaline environment in ing acute respiratory failure in a uremic patient. Am J those areas as a result of higher ventilation-to-perfu- Kidney Dis 2006;47:e47–53. sion ratios and hence lower partial pressures of CO . 9 Nizami MA, Gerntholtz T, Swanepoel CR. The role 2 of bone scanning in the detection of metastatic cal- cification: a case report. Clin Nucl Med Conclusions 2000;25:407–9. Although patients with metastatic pulmonary calcifi- 10 Conger JD, Hammond WS, Alfrey AC, Contiguglia cations are usually asymptomatic, calcium, phosphate, SR, Stanford RE, Huffer WE. Pulmonary calcifica- and levels should be monitored, tion in chronic dialysis patients: clinical and patho- and abnormalities should be treated to avoid progres- logical studies. Ann Intern Med 1975;83:330–6. sion to calciphylaxis. Few options exist for treating 11 Matsuo T, Tsukamoto Y, Tamura M, et al. Acute res- calciphylaxis, and the outcome is generally poor. piratory failure due to “pulmonary calciphylaxis” in a Beyzaei et al. 117

maintenance haemodialysis patient. Nephron 16 Kato A, Odamaki M, Takita T, Maruyama Y, 2001;87:75–9. Kumagai H, Hishida A. Association between 12 Strumia R, Lombardi AR, Bedani PL, Perini L. Be- interleukin-6 and carotid atherosclerosis in hemodi- nign nodular calcification and calciphylaxis in a alysis patients. Kidney Int 2002;61:1143–52. haemodialysed patient. J Eur Acad Dermatol Venereol 17 Nitta K, Akiba T, Uchida K, et al. Serum 1998;11:69–71. osteoprotegerin levels and the extent of vascular cal- 13 Mazhar AR, Johnson RJ, Gillen D, et al. Risk factors cification in haemodialysis patients. Nephrol Dial and mortality associated with calciphylaxis in end- Transplant 2004;19:1886–9. stage renal disease. Kidney Int 2001;60:324–32. 14 Dear J, Brookes J, Mansell M, Laing C. Calciphy- Corresponding author: laxis. Lancet 2003;362:1707. Fredric Finkelstein, MD, 136 Sherman Avenue, New 15 Wilmer WA, Magro CM. Calciphylaxis: emerging Haven, Connecticut 06511 U.S.A. concepts in prevention, diagnosis, and treatment. E-mail: Semin Dial 2002;15:172–86. [email protected]