Pulmonary alveolar proteinosis in a kidney transplant: a rare complication of sirolimus

Kadikoy, Hüseyin; Paolini, Michael A.; Achkar, Katafan; Suki, Wadi N.; Gaber, A. Osama; Anwar, Nabeel; Jeroudi, Abdallah; Barrios, Roberto; Abdellatif, Abdul

doi:10.1093/ndt/gfq265

Cited by 23 publications

(17 citation statements)

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“…The striking lack of involvement of the native lung in recipients of single-lung transplantation may indicate an alveolar macrophage injury linked to a pathogenic process located specifically in the graft; however, this remains to be determined. In addition, the promoting role of immunosuppressive therapy has previously been evoked in cases of symptomatic PAP reported to develop in lung-or kidney-transplant recipients [2][3][4]10], including almost all well-described cases related to mammalian target of rapamycin inhibitor (mTOR inh) use [4,10].…”

Section: Discussionmentioning

confidence: 99%

Secondary pulmonary alveolar proteinosis after lung transplantation: a single-centre series

et al. 2017

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Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by accumulation of surfactant in alveolar space related to alveolar macrophage dysfunction. PAP occurs in three clinically distinct forms: autoimmune PAP (90% of cases), secondary PAP and genetic PAP [1]. Secondary PAP may be related to immunosuppressive disorders, with few cases associated with solid-organ transplant [1]. Indeed, to our knowledge, only five cases of symptomatic PAP secondary to lung transplantation have been reported [2][3][4].Here, we report a series of four new cases of PAP in lung transplantation recipients, with death associated with PAP-onset in all cases. One patient showed impaired granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling in the absence of auto-antibodies, which argues for similar mechanisms as in autoimmune PAP. A specific enhanced risk associated with lung transplantation was also suggested by the lack of native lung involvement in single-lung transplantation recipients. Patient oneA 66-year-old man with idiopathic pulmonary fibrosis (IPF) underwent left single-lung transplantation from a 34-year-old male smoker. The immediate post-operative course was uneventful, with primary graft dysfunction determined to be grade 0. On post-operative day 72, acute rejection (grade A2B0) [5] was diagnosed without complement component 4d (C4d) staining. Donor-specific antibodies were detected by Luminex (human leukocyte antigen DQ7 (HLA-DQ7); mean fluorescent intensity (MFI)=4030) and steroid boluses were administered followed, on post-operative day 101, by anti-thymocyte globulins due to the persistence of histologically proven acute rejection (grade A2B0) [5]. Subsequent transbronchial biopsies ( post-operative day 134) showed complete resolution of the acute rejection episode (grade A0B0). Furthermore, bronchoalveolar lavage fluid (BALF) analysis did not show parasitic (Pneumocystis jirovecii), mycological, viral (using multiplex PCR assay), or bacterial infection (including Nocardia), and cardiac ultrasonography revealed normal left-ventricular function. Nevertheless, in parallel with histological resolution of the steroid-resistant acute rejection episode, repeat computed tomography (CT) scans showed progressively worsening lung opacities from post-operative day 129, with a "crazy-paving" pattern located exclusively in the graft (figure 1a). Re-examination of transbronchial biopsies from post-operative day 134 (figure 1b) and a new BALF analysis stained with periodic acid-Schiff (PAS) reagent (figure 1c) led to a diagnosis of PAP. Anti-(GM-CSF) antibodies were absent and the possibility of impaired GM-CSF signalling was investigated using a recently described test based on the ability of GM-CSF to rapidly increase cell-surface CD11b levels on neutrophils in flow cytometry (reflected by a CD11b stimulation index) [6]. The GM-CSF stimulation index in patient one was very low, with a value of seven as compared to values of 101, 55 and 102 in three stable lung-transplantation recipients used as positive ...

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Section: Discussionmentioning

confidence: 99%

Secondary pulmonary alveolar proteinosis after lung transplantation: a single-centre series

et al. 2017

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“…A failure of scavenging mechanisms lies at the heart of both forms. The prognosis of S-PAP can be unpredictable[2] and the outcome is generally regarded as much worse than that of the autoimmune variety, with a median survival time of around 20 months. [5]…”

Section: Discussionmentioning

confidence: 99%

“…The primary PAP (P-PAP) accounts for approximately 90% of all cases and appears to be mediated through a circulating neutralizing antibody (anti granulocyte-macrophage colony-stimulating factor (GM-CSF) immunoglobulin neutralizing immunoglobulin G antibody). [2] Since GM-CSF normally plays a vital role in the catabolism of surfactant by alveolar macrophages, its functional deficiency allows surfactant to accumulate.…”

Section: Introductionmentioning

confidence: 99%

“…PAP that occurs as a consequence of immunosuppressive agents also falls into this category. Although cyclosporin-A has been causally linked with PAP[3] and rare cases of alveolar proteinosis have been reported due to sirolimus,[2] a Medline/PubMed search revealed no occurrence of PAP in renal transplant patients that occurred as a consequence of cyclosporine-mycophenolate combination therapy.…”

Section: Introductionmentioning

confidence: 99%

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Pulmonary alveolar proteinosis due to mycophenolate and cyclosporine combination therapy in a renal transplant recipient

Hasan

Ram²,

Swamy

2014

Lung India

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Pulmonary alveolar proteinosis (PAP) is an orphan disease characterized by the accumulation of excess of surfactant within alveoli and bronchioles. The primary form of PAP (P-PAP; also referred to as idiopathic or autoimmune) is the most common form. It is mediated through a circulating neutralizing antibody against granulocyte-macrophage colony-stimulating factor. Secondary PAP (S-PAP) can be induced by a host of inciting agents and is far more liable to progress to terminal respiratory failure. We describe a rare case of S-PAP occurring in a renal transplant recipient due to mycophenolate and cyclosporine combination-therapy, which resolved spontaneously following withdrawal of these drugs.

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“…Idiopathic PAP represents 90% of cases and is associated with circulating GM-CSF-neutralizing antibodies. Secondary forms occur in the setting of hematological malignancies, inhalation of toxic dust, fumes, or gases, immunosuppression due to infections or drugs, such as sirolimus [16, 17], and lysinuric protein intolerance, an autosomal recessive disease caused by defective transport of cationic amino acids [18]. These disorders can impair alveolar macrophage function, leading to surfactant accumulation [9].…”

Section: Discussionmentioning

confidence: 99%

Potential association between membranous nephropathy and sargramostim therapy for pulmonary alveolar proteinosis

Sewaralthahab

Rennke

Sewaralthahab

et al. 2014

CNCS

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We present the case of a 43-year-old woman with a diagnosis of pulmonary alveolar proteinosis, on chronic treatment with sargramostim, a recombinant granulocyte-macrophage colony-stimulating factor, who presented with the nephrotic syndrome secondary to biopsy-proven membranous nephropathy. We discuss potential underlying mechanisms, including speculated effects of sargramostim on mesangial cells and the kidney resident macrophages, and review the existing literature on the potential association between these two disorders.

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Pulmonary alveolar proteinosis in a kidney transplant: a rare complication of sirolimus

Cited by 23 publications

References 10 publications

Secondary pulmonary alveolar proteinosis after lung transplantation: a single-centre series

Secondary pulmonary alveolar proteinosis after lung transplantation: a single-centre series

Pulmonary alveolar proteinosis due to mycophenolate and cyclosporine combination therapy in a renal transplant recipient

Potential association between membranous nephropathy and sargramostim therapy for pulmonary alveolar proteinosis

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