A 31-year-old female patient with chronic kidney disease presenting with persistent cough

Discussion

Our patient had bilateral metastatic calcification secondary to ESRD. Parenchymal pulmonary calcifications may be classified into two types: dystrophic and metastatic. Dystrophic calcification is due to the deposition of crystalline hydroxyapatite calcium salt in areas of damaged lung tissues, which is usually secondary to any post-inflammatory process, e.g. tuberculosis. The serum levels of calcium and phosphate are usually normal in these situations. Conversely, metastatic pulmonary calcification (MPC) is associated with high serum levels of calcium and phosphate, causing the deposition of calcium salts in the alveolar epithelial basement membrane over a span of time inside the lung parenchyma [6–8]. Although rare, this metabolic lung disorder is often associated with ESRD. Besides being seen in patients with ESRD on dialysis, MPC can be found in primary hyperparathyroidism, granulomatous diseases like sarcoidosis, milk-alkali syndrome, parathyroid carcinoma or any malignancies like multiple myeloma and lymphoma [9].

There are four major possible predisposing factors that may contribute to MPC in dialysis patients. First, it has been postulated that chronic acidosis in the inter-dialytic interval can leach calcium from bone, leading to its deposition in soft tissue during post-dialysis alkalosis. Secondly, intermittent alkalosis favours deposition of calcium salts by increasing the activity of alkaline phosphatase, which catalyses the release of phosphates thereby leading to calcium-phosphate deposition. Thirdly, secondary hyperparathyroidism in CKD tends to cause bone resorption and intracellular hypercalcaemia. Parathormone, vitamin D and uraemia act like sensitising agents and promote calcification. Finally, low glomerular filtration rate can cause hyperphosphataemia and an elevated calcium-phosphorus product. Haemodialysis for chronic renal insufficiency seems to be the leading benign cause that may precipitate to pulmonary calcifications. The lung is particularly susceptible to metastatic calcification as the pH of blood in the lung is more alkalotic compared with other organs because of the active carbon dioxide removal process at the lung apex and upper lobe as compared to other lung regions [10]. MPC can be present even with normal levels of calcium, magnesium and phosphate [11].

Conventionally, patients with MPC are asymptomatic; sometimes symptoms can be mild dyspnoea, rarely acute respiratory distress. Pulmonary function testing shows a restrictive lung pattern, which corresponds to MPC in lungs [7, 11]. Pulmonary artery pressures do not have any relation to MPC [12]. Chest radiographs are generally normal with occasional presence of confluent or patchy airspace opacities, discrete calcified nodules or diffuse interstitial process. HRCT of the thorax is more sensitive, exhibiting calcification in approximately 60% of cases [13]. Usually, multiple poorly defined centrilobular nodules, diffuse or patchy areas of ground-glass opacities or consolidation may be present. The diagnosis of MPC can be made by characteristic high-attenuation signals in combination with pulmonary and vascular calcification. The relative stability and central distribution of these pulmonary infiltrates, despite treatment, helps in differentiating MPC from pulmonary oedema or infection and goes against organising pneumonia [6]. Radionuclide imaging (with technetium-99m dicarboxypropane diphosphonate (Tc-99m DPD)) is reckoned as the most sensitive technique for early detection of MPC. A study by Rajkovača et al. [14] suggests that scintigraphy with Tc-99m DPD in patients with chronic renal failure undergoing long-term haemodialysis, alongside a reduced pulmonary function test, helps in early detection of pulmonary calcification.

Rarely, there might be dense bilateral consolidation without calcification; however, density of opacities might not be high enough to suggest calcification. Differential diagnosis should always include infection, as these patients are usually immunosuppressed [8]. The density of opacities is not sufficiently high to suggest calcification in most of the reported cases and might need high-kilovoltage and low-contrast techniques for detection [15–17].

Our patient was relatively asymptomatic with abnormal chest imaging, corresponding to what has been published in the literature. Pulmonary function tests revealed a mild restrictive defect with severe reduction in the gas transfer indices. No technetium studies were done as the facility was not available in the centre. The HRCT scan of thorax features, particularly the presence of consolidation, was not typical of non-specific interstitial pneumonia. Lung biopsy would have established the diagnosis, as calcification is often intracellular and might not be apparent on the HRCT scan. However, because of the low transfer factor, the patient was a high-risk case for surgical lung biopsy. A transbronchial biopsy would not have been useful because of the small size of the sample and crush artefacts. No iron staining was done on the BAL fluid as there was no history of haemoptysis, the BAL fluid was clear and there was no suspicion of pulmonary haemosiderosis. No periodic acid–Schiff stain was done, as the physical appearance and cellular profile were against pulmonary alveolar proteinosis. Moreover, the patient had minimal dyspnoea with no history of fever or weight loss. There was no clinical suggestion of fluid overload or heart failure.

Patients with MPC are rarely symptomatic; in symptomatic patients the treatment goal is to normalise the calcium and phosphate levels, which often helps in alleviating the symptoms. Biphosphonates, calcimimetics, parathyroidectomy and increase in the frequency of dialysis have shown success in some patients. Renal transplantation in renal failure patients is another option, but worsening of MPC has also been reported despite successful transplantation [1, 6].