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A 59-Year-Old Man With Chronic Kidney Disease After Kidney Transplantation Presents With Chronic Dyspnea
[
CHEST Pearls
]
A 59-Year-Old Man With Chronic Kidney Disease After Kidney Transplantation Presents With Chronic Dyspnea Patrick Duncan, MD; Stephanie Cull, MD; Palmi Shah, MD; and Amie Gamino, MD
A 59-year-old man presented to the ED with a chief complaint of shortness of breath. His past medical history was significant for end-stage renal disease secondary to lithium toxicity, immunosuppression subsequent to cadaveric renal transplantation, bipolar disorder, and hypertension. His shortness of breath had begun 6 months previously and was initially intermittent; it then progressed to constant shortness of breath over the few weeks before presentation. He had no fever, hemoptysis, or chest pain. The patient was admitted to hospital for further evaluation. CHEST 2020; 157(1):e9-e12
CASE PRESENTATION:
Physical Examination Findings Initial vital signs were notable for a BP of 125/ 88 mm Hg, heart rate of 63 beats/min, temperature of 36.1 C, respiratory rate of 18 breaths/min, and oxygen saturation (as measured by pulse oximetry; SpO2) of 93% while receiving supplemental oxygen at 2 L/min. The patient appeared to be in mild respiratory distress, tachypneic, and had difficulty completing full sentences. There were decreased breath sounds and expiratory wheezing bilaterally on auscultation. Heart sounds were normal. The remaining physical examination results were unremarkable.
Diagnostic Studies Arterial blood gas results on presentation were as follows: pH 7.43, PCO2 32 mm Hg, PO2 70 mm Hg. CBC counts were normal. The chemistry panel was notable
AFFILIATIONS: From the Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine (Drs Duncan, Cull, and Gamino), and the Department of Diagnostic Radiology and Nuclear Medicine (Dr Shah), Rush University Medical Center, Chicago, IL. CORRESPONDENCE TO: Patrick Duncan, MD, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Rush
chestjournal.org
Figure 1 – Chest radiograph showing bilateral perihilar ground-glass opacities.
University Medical Center, 600 S Paulina St, Chicago, IL 60612; e-mail: [email protected] Copyright Ó 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: https://doi.org/10.1016/j.chest.2019.08.1918
e9
Figure 2 – CT angiography of the chest, showing bilateral apical groundglass nodules.
for hypocalcemia (6.6 mg/dL) and creatinine elevation (2.35 mg/dL) from baseline (1.3 mg/dL). Phosphorus was elevated (8.7 mg/dL). Radiography of the chest demonstrated bilateral upper lobe-predominant groundglass opacities (Fig 1). A CT scan of the chest showed bilateral upper lobepredominant centrilobular ground-glass irregular nodules, possibly suggesting an infectious or inflammatory process in the setting of immunosuppression (Fig 2). Urine tests for the presence of Histoplasma antigen, Blastomyces antigen, Streptococcus pneumoniae antigen, and Legionella pneumophila antigen, as well as sputum culture and blood cultures, produced negative results. Considering the findings on CT imaging of the chest in this patient, who is immunocompromised, bronchoscopy with BAL was performed. Alveolar fluid studies all produced negative results, including Gram
e10 CHEST Pearls
Figure 3 – Bone scan demonstrating diffuse mild uptake in upper/ midthoracic region bilaterally.
stain, aerobic culture, anaerobic culture, fungal smear/ culture, acid-fast bacilli smear/culture, galactomannan antigen, Pneumocystis jirovecii PCR, and cytomegalovirus PCR. A left upper lobe transbronchial biopsy was obtained and revealed extensive dystrophic calcifications along the alveolar septa. Given the findings on imaging and histology, a 99mTc bone scan was done to establish the diagnosis. This showed diffuse mild uptake in the upper/midthoracic region bilaterally, corresponding to the changes that were seen on the CT scan (Fig 3).
Question: What is the diagnosis?
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157#1 CHEST JANUARY 2020
]
Diagnosis: Metastatic pulmonary calcinosis Discussion Epidemiology
Metastatic pulmonary calcinosis (MPC) is most frequently associated with chronic renal failure requiring dialysis. MPC is found on autopsy in 60% to 75% of patients who received dialysis during their lifetime. The frequency of MPC being found on autopsy is declining over time, with the likely explanation being improvement in calcium and phosphate balance with vitamin D analogs and phosphate binders. Other disorders that have been associated with MPC include primary hyperparathyroidism, multiple myeloma, and rarely leukemia. Pathophysiology/Etiology
Pathologic calcification refers to a process in which there is deposition of calcium salts in soft tissue. Common locations include the peripheral vascular system, lungs, kidneys, stomach, and heart. The process can be divided further depending on the underlying characteristics of the tissue where the salt is deposited. Metastatic calcification occurs in healthy tissue; dystrophic calcification occurs in injured tissue. Elevated calciumphosphate product (> 70 mg2/dL2) has traditionally been correlated with metastatic calcification; however, this product is just one of multiple influencing factors. Metastatic calcification tends to occur in tissue that excretes acid and has an alkaline compartment. It is thought that the degree of alkalization is inversely correlated to the calcium-phosphate product required for precipitation of the salts out of the serum. Uremia may also play a role in accelerating metastatic calcification. The exact mechanism is not known, but it has been theorized that uremia induces a change in tissue protein configuration, making the tissue more susceptible to calcification. Patients with end-stage renal disease (ESRD) who are undergoing hemodialysis have a proclivity to develop metastatic pulmonary calcinosis due to a multitude of metabolic derangements. Patients with ESRD develop acidosis between dialysis sessions, which leaches phosphate and calcium from bone. Furthermore, infusion of bicarbonate solution used with hemodialysis causes transient alkalosis, which then encourages precipitation of calcium-phosphate salt out of the serum and into tissue. The leaching process is exacerbated by low 1,25-vitamin D levels, causing hypocalcemia, in turn
chestjournal.org
triggering an elevation in parathyroid hormone and increased bone turnover. Patients with ESRD are also prone to uremia, which worsens calcification as previously mentioned. Patients with ESRD or nephrotic syndrome also have low serum protein levels due to glomerular disease, which results in an increase in the serum of free calcium available for precipitation. Clinical Manifestations
Metastatic calcification most commonly targets the lungs. On biopsy, lung calcification has been found to affect the alveoli, alveolar capillaries, bronchi, and pulmonary vessels. The upper and middle lung lobes tend to be affected more than the lower lobes. This phenomenon is explained by the upper lung lobes being relatively more alkaline. The higher ventilation_ ratio leads to lower PCO2 in blood _ Q) perfusion (V= serving the upper lungs, therefore encouraging precipitation of calcium salt. MPC is frequently asymptomatic; however, restrictive lung disease with diffusion defects can occur. The degree of calcification seen on imaging does not correlate with the severity of symptoms, or with restriction and diffusion defects found on pulmonary function testing. Chest radiographs can detect opacities associated with calcification; however, chest radiography alone cannot differentiate MPC from other pathologic pulmonary processes. High-resolution CT imaging can help identify pulmonary calcifications, and there are three described patterns of MPC seen on CT imaging: (1) multiple diffuse calcified nodules, (2) diffuse or patchy areas of ground-glass opacification, and (3) confluent highattenuation parenchymal consolidation with lobar distribution. The most sensitive imaging modality for detection of MPC is the 99mTc bone scan. For the patient described here, the differential based on imaging before the bone scan was infection, hypersensitivity pneumonitis, or metastatic pulmonary calcinosis. Thus, imaging was ordered to differentiate between these diseases. Treatment and Outcomes
Treatment of symptomatic MPC is currently focused on adjusting the calcium-phosphate product to its normal range; however, the optimal treatment for the disease is not known. Initial treatment usually includes the use of bisphosphonates and phosphate binders. Vitamin D supplementation for secondary or tertiary hyperparathyroidism is controversial. Vitamin D decreases the hyperphosphatemia mediated by elevated
e11
parathyroid hormone; however, it will also increase serum calcium. In symptomatic patients with MPC and hyperparathyroidism, parathyroidectomy is warranted if medication cannot control disease progression. For patients with ESRD, the modality and frequency of dialysis may also influence progression of MPC. Symptomatic MPC warrants an increase in the dialysis dose. Some evidence suggests that the superior control of phosphate and uremia with nocturnal hemodialysis results in better outcomes compared with three-timesweekly hemodialysis. There has been conflicting evidence as to whether renal transplantation improves or worsens calcification.
patients with ESRD with chronic dyspnea of unclear etiology. 3. Elevated serum calcium-phosphate product (> 70 mg2/ dL2) should suggest MPC; however, MPC can also occur with normal-range calcium-phosphate product. 4. Attempts to adjust the calcium-phosphate product to normal levels are the mainstay of prevention and treatment. This can be done via phosphate binders, bisphosphonates, and by increasing the frequency of dialysis for patients with ESRD.
Acknowledgments Financial/nonfinancial disclosures: None declared.
Overall, most patients are asymptomatic and no treatment is warranted until symptoms arise. The cause of mortality in patients with MPC is more commonly related to other complications of ESRD and not to MPC itself.
Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
Clinical Course
Kuzela DC, Huffer WE, Conger JD, Winter SD, Hammond WS. Soft tissue calcification in chronic dialysis patients. Am J Pathol. 1977;86(2): 403-424.
This patient was treated with supportive care and on discharge was lost to follow-up. One year later he was admitted for shortness of breath. A repeat CT scan of the chest showed there was no progression of metastatic calcinosis. The patient left against medical advice before investigation was completed and was again lost to follow-up.
Clinical Pearls 1. MPC commonly affects patients with ESRD and although frequently asymptomatic, should be considered in the differential diagnosis of chronic dyspnea in patients with ESRD. 2. MPC is difficult to differentiate from other pulmonary diseases with chest radiographs and CT imaging, whereas bone scans can establish the diagnosis in
e12 CHEST Pearls
Suggested Readings Conger JD, Hammond WS, Alfrey AC, Contiguglia SR, Stanford RE, Huffer WE. Pulmonary calcification in chronic dialysis patients: clinical and pathologic studies. Ann Intern Med. 1975;83(3):330-336.
Bein ME, Lee DB, Mink JH, Dickmeyer J. Unusual case of metastatic pulmonary calcification. AJR Am J Roentgenol. 1979;132(5):812-816. Justrabo E, Genin R, Rifle G. Pulmonary metastatic calcification with respiratory insufficiency in patients on maintenance haemodialysis. Thorax. 1979;34(3):384-388. Sanders C, Frank MS, Rostand SG, Rutsky EA, Barnes GT, Fraser RG. Metastatic calcification of the heart and lungs in end-stage renal disease: detection and quantification by dual-energy digital chest radiography. AJR Am J Roentgenol. 1987;149(5):881-887. Hartman TE, Muller NL, Primack SL, et al. Metastatic pulmonary calcification in patients with hypercalcemia: findings on chest radiographs and CT scans. AJR Am J Roentgenol. 1994;162(4):799-802. Chan ED, Morales DV, Welsh CH, McDermott MT, Schwarz MI. Calcium deposition with or without bone formation in the lung. Am J Respir Crit Care Med. 2002;165(12):1654-1669. Belem LC, Zanetti G, Souza AS Jr, et al. Metastatic pulmonary calcification: state-of-the-art review focused on imaging findings. Respir Med. 2014;108(5):668-676. Walter JM, Stanley M, Singer BD. Metastatic pulmonary calcification and end-stage renal disease. Cleve Clin J Med. 2017;84(9):668-669.
[
157#1 CHEST JANUARY 2020
]
CHEST Pearls
]
A 59-Year-Old Man With Chronic Kidney Disease After Kidney Transplantation Presents With Chronic Dyspnea Patrick Duncan, MD; Stephanie Cull, MD; Palmi Shah, MD; and Amie Gamino, MD
A 59-year-old man presented to the ED with a chief complaint of shortness of breath. His past medical history was significant for end-stage renal disease secondary to lithium toxicity, immunosuppression subsequent to cadaveric renal transplantation, bipolar disorder, and hypertension. His shortness of breath had begun 6 months previously and was initially intermittent; it then progressed to constant shortness of breath over the few weeks before presentation. He had no fever, hemoptysis, or chest pain. The patient was admitted to hospital for further evaluation. CHEST 2020; 157(1):e9-e12
CASE PRESENTATION:
Physical Examination Findings Initial vital signs were notable for a BP of 125/ 88 mm Hg, heart rate of 63 beats/min, temperature of 36.1 C, respiratory rate of 18 breaths/min, and oxygen saturation (as measured by pulse oximetry; SpO2) of 93% while receiving supplemental oxygen at 2 L/min. The patient appeared to be in mild respiratory distress, tachypneic, and had difficulty completing full sentences. There were decreased breath sounds and expiratory wheezing bilaterally on auscultation. Heart sounds were normal. The remaining physical examination results were unremarkable.
Diagnostic Studies Arterial blood gas results on presentation were as follows: pH 7.43, PCO2 32 mm Hg, PO2 70 mm Hg. CBC counts were normal. The chemistry panel was notable
AFFILIATIONS: From the Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine (Drs Duncan, Cull, and Gamino), and the Department of Diagnostic Radiology and Nuclear Medicine (Dr Shah), Rush University Medical Center, Chicago, IL. CORRESPONDENCE TO: Patrick Duncan, MD, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Rush
chestjournal.org
Figure 1 – Chest radiograph showing bilateral perihilar ground-glass opacities.
University Medical Center, 600 S Paulina St, Chicago, IL 60612; e-mail: [email protected] Copyright Ó 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: https://doi.org/10.1016/j.chest.2019.08.1918
e9
Figure 2 – CT angiography of the chest, showing bilateral apical groundglass nodules.
for hypocalcemia (6.6 mg/dL) and creatinine elevation (2.35 mg/dL) from baseline (1.3 mg/dL). Phosphorus was elevated (8.7 mg/dL). Radiography of the chest demonstrated bilateral upper lobe-predominant groundglass opacities (Fig 1). A CT scan of the chest showed bilateral upper lobepredominant centrilobular ground-glass irregular nodules, possibly suggesting an infectious or inflammatory process in the setting of immunosuppression (Fig 2). Urine tests for the presence of Histoplasma antigen, Blastomyces antigen, Streptococcus pneumoniae antigen, and Legionella pneumophila antigen, as well as sputum culture and blood cultures, produced negative results. Considering the findings on CT imaging of the chest in this patient, who is immunocompromised, bronchoscopy with BAL was performed. Alveolar fluid studies all produced negative results, including Gram
e10 CHEST Pearls
Figure 3 – Bone scan demonstrating diffuse mild uptake in upper/ midthoracic region bilaterally.
stain, aerobic culture, anaerobic culture, fungal smear/ culture, acid-fast bacilli smear/culture, galactomannan antigen, Pneumocystis jirovecii PCR, and cytomegalovirus PCR. A left upper lobe transbronchial biopsy was obtained and revealed extensive dystrophic calcifications along the alveolar septa. Given the findings on imaging and histology, a 99mTc bone scan was done to establish the diagnosis. This showed diffuse mild uptake in the upper/midthoracic region bilaterally, corresponding to the changes that were seen on the CT scan (Fig 3).
Question: What is the diagnosis?
[
157#1 CHEST JANUARY 2020
]
Diagnosis: Metastatic pulmonary calcinosis Discussion Epidemiology
Metastatic pulmonary calcinosis (MPC) is most frequently associated with chronic renal failure requiring dialysis. MPC is found on autopsy in 60% to 75% of patients who received dialysis during their lifetime. The frequency of MPC being found on autopsy is declining over time, with the likely explanation being improvement in calcium and phosphate balance with vitamin D analogs and phosphate binders. Other disorders that have been associated with MPC include primary hyperparathyroidism, multiple myeloma, and rarely leukemia. Pathophysiology/Etiology
Pathologic calcification refers to a process in which there is deposition of calcium salts in soft tissue. Common locations include the peripheral vascular system, lungs, kidneys, stomach, and heart. The process can be divided further depending on the underlying characteristics of the tissue where the salt is deposited. Metastatic calcification occurs in healthy tissue; dystrophic calcification occurs in injured tissue. Elevated calciumphosphate product (> 70 mg2/dL2) has traditionally been correlated with metastatic calcification; however, this product is just one of multiple influencing factors. Metastatic calcification tends to occur in tissue that excretes acid and has an alkaline compartment. It is thought that the degree of alkalization is inversely correlated to the calcium-phosphate product required for precipitation of the salts out of the serum. Uremia may also play a role in accelerating metastatic calcification. The exact mechanism is not known, but it has been theorized that uremia induces a change in tissue protein configuration, making the tissue more susceptible to calcification. Patients with end-stage renal disease (ESRD) who are undergoing hemodialysis have a proclivity to develop metastatic pulmonary calcinosis due to a multitude of metabolic derangements. Patients with ESRD develop acidosis between dialysis sessions, which leaches phosphate and calcium from bone. Furthermore, infusion of bicarbonate solution used with hemodialysis causes transient alkalosis, which then encourages precipitation of calcium-phosphate salt out of the serum and into tissue. The leaching process is exacerbated by low 1,25-vitamin D levels, causing hypocalcemia, in turn
chestjournal.org
triggering an elevation in parathyroid hormone and increased bone turnover. Patients with ESRD are also prone to uremia, which worsens calcification as previously mentioned. Patients with ESRD or nephrotic syndrome also have low serum protein levels due to glomerular disease, which results in an increase in the serum of free calcium available for precipitation. Clinical Manifestations
Metastatic calcification most commonly targets the lungs. On biopsy, lung calcification has been found to affect the alveoli, alveolar capillaries, bronchi, and pulmonary vessels. The upper and middle lung lobes tend to be affected more than the lower lobes. This phenomenon is explained by the upper lung lobes being relatively more alkaline. The higher ventilation_ ratio leads to lower PCO2 in blood _ Q) perfusion (V= serving the upper lungs, therefore encouraging precipitation of calcium salt. MPC is frequently asymptomatic; however, restrictive lung disease with diffusion defects can occur. The degree of calcification seen on imaging does not correlate with the severity of symptoms, or with restriction and diffusion defects found on pulmonary function testing. Chest radiographs can detect opacities associated with calcification; however, chest radiography alone cannot differentiate MPC from other pathologic pulmonary processes. High-resolution CT imaging can help identify pulmonary calcifications, and there are three described patterns of MPC seen on CT imaging: (1) multiple diffuse calcified nodules, (2) diffuse or patchy areas of ground-glass opacification, and (3) confluent highattenuation parenchymal consolidation with lobar distribution. The most sensitive imaging modality for detection of MPC is the 99mTc bone scan. For the patient described here, the differential based on imaging before the bone scan was infection, hypersensitivity pneumonitis, or metastatic pulmonary calcinosis. Thus, imaging was ordered to differentiate between these diseases. Treatment and Outcomes
Treatment of symptomatic MPC is currently focused on adjusting the calcium-phosphate product to its normal range; however, the optimal treatment for the disease is not known. Initial treatment usually includes the use of bisphosphonates and phosphate binders. Vitamin D supplementation for secondary or tertiary hyperparathyroidism is controversial. Vitamin D decreases the hyperphosphatemia mediated by elevated
e11
parathyroid hormone; however, it will also increase serum calcium. In symptomatic patients with MPC and hyperparathyroidism, parathyroidectomy is warranted if medication cannot control disease progression. For patients with ESRD, the modality and frequency of dialysis may also influence progression of MPC. Symptomatic MPC warrants an increase in the dialysis dose. Some evidence suggests that the superior control of phosphate and uremia with nocturnal hemodialysis results in better outcomes compared with three-timesweekly hemodialysis. There has been conflicting evidence as to whether renal transplantation improves or worsens calcification.
patients with ESRD with chronic dyspnea of unclear etiology. 3. Elevated serum calcium-phosphate product (> 70 mg2/ dL2) should suggest MPC; however, MPC can also occur with normal-range calcium-phosphate product. 4. Attempts to adjust the calcium-phosphate product to normal levels are the mainstay of prevention and treatment. This can be done via phosphate binders, bisphosphonates, and by increasing the frequency of dialysis for patients with ESRD.
Acknowledgments Financial/nonfinancial disclosures: None declared.
Overall, most patients are asymptomatic and no treatment is warranted until symptoms arise. The cause of mortality in patients with MPC is more commonly related to other complications of ESRD and not to MPC itself.
Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
Clinical Course
Kuzela DC, Huffer WE, Conger JD, Winter SD, Hammond WS. Soft tissue calcification in chronic dialysis patients. Am J Pathol. 1977;86(2): 403-424.
This patient was treated with supportive care and on discharge was lost to follow-up. One year later he was admitted for shortness of breath. A repeat CT scan of the chest showed there was no progression of metastatic calcinosis. The patient left against medical advice before investigation was completed and was again lost to follow-up.
Clinical Pearls 1. MPC commonly affects patients with ESRD and although frequently asymptomatic, should be considered in the differential diagnosis of chronic dyspnea in patients with ESRD. 2. MPC is difficult to differentiate from other pulmonary diseases with chest radiographs and CT imaging, whereas bone scans can establish the diagnosis in
e12 CHEST Pearls
Suggested Readings Conger JD, Hammond WS, Alfrey AC, Contiguglia SR, Stanford RE, Huffer WE. Pulmonary calcification in chronic dialysis patients: clinical and pathologic studies. Ann Intern Med. 1975;83(3):330-336.
Bein ME, Lee DB, Mink JH, Dickmeyer J. Unusual case of metastatic pulmonary calcification. AJR Am J Roentgenol. 1979;132(5):812-816. Justrabo E, Genin R, Rifle G. Pulmonary metastatic calcification with respiratory insufficiency in patients on maintenance haemodialysis. Thorax. 1979;34(3):384-388. Sanders C, Frank MS, Rostand SG, Rutsky EA, Barnes GT, Fraser RG. Metastatic calcification of the heart and lungs in end-stage renal disease: detection and quantification by dual-energy digital chest radiography. AJR Am J Roentgenol. 1987;149(5):881-887. Hartman TE, Muller NL, Primack SL, et al. Metastatic pulmonary calcification in patients with hypercalcemia: findings on chest radiographs and CT scans. AJR Am J Roentgenol. 1994;162(4):799-802. Chan ED, Morales DV, Welsh CH, McDermott MT, Schwarz MI. Calcium deposition with or without bone formation in the lung. Am J Respir Crit Care Med. 2002;165(12):1654-1669. Belem LC, Zanetti G, Souza AS Jr, et al. Metastatic pulmonary calcification: state-of-the-art review focused on imaging findings. Respir Med. 2014;108(5):668-676. Walter JM, Stanley M, Singer BD. Metastatic pulmonary calcification and end-stage renal disease. Cleve Clin J Med. 2017;84(9):668-669.
[
157#1 CHEST JANUARY 2020
]