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Volume: 12 Issue: 4 August 2014


Osseus Metaplasia in Kidney Allografts as a Paradigm of Regenerative Medicine Principles

We report the sixth case of osseous metaplasia that has occurred in the last 5 years, after a deceased-donor renal transplant was performed on a young man. While its clinical significance is unclear and probably irrelevant, osseous metaplasia is one of the most relevant principles of regenerative medicine, where every bodily district contains progenitor cells that can generate cells specific to the germ layer from which they come. After the Case Report, we review the literature and speculate on the underlying pathophysiology of osseous metaplasia. Available data seem to support the hypothesis that osteogenic precursor cells, inducing factors, and a suitable environment are key for osseous metaplasia.

Key words : Renal transplant, Biopsy, Osseous metaplasia, Regenerative medicine


Osseous metaplasia (OM) is an exceptional finding which has been described in seriously damaged renal allografts as well as in other districts of the urinary tract. It is a process resulting in the formation of bone tissue that is often atypical, at an extraskeletal location. Notably, it should be differentiated from simple calcification, which instead is synonymous with the mere formation of calcium-based salts and crystals within cells and tissue.1

Bone formation results from the activity of osteoblasts and osteoclasts and the addition of minerals and salts, yet the mechanisms are not fully understood.2 Calcium compounds must be present for ossification to take place. As osteoblasts do not make these minerals, they must take them from the blood and deposit them in the bone. As for normal ossification, the exact mechanisms by which OM development is triggered remains unclear; however, heterotopia, dystrophic calcifications, ossification of damaged areas, metastatic calcification, and metaplasia in healing tissue may be considered predisposing factors. While its clinical significance remains unclear, OM represents a formidable paradigm of one of the most relevant principles of regenerative medicine, namely that every bodily district contains progenitor cells that can generate cells specific to the germ layer from which they derive.

To the best of our knowledge, 5 cases of OM have been reported in the English literature, all occurring in patients aged between 15 and 43 years, within 24 months of the transplant.3-7 Interestingly, OM developed in concomitance with some form of rejection and chronic ischemia, and has been described in the cortex in 2 cases,3,4 in both cortex and medulla in 2,5,6 and in the ureter in the remaining case.7 We herein report a further case of OM observed 5 years after renal transplant to substantiate our speculation.

Case Report

A 22-year-old African American man with end-stage renal disease secondary to focal segmental glomerulosclerosis and concomitant obesity and renal osteodystrophy received a renal transplant in February 2006. Before receiving the transplant, the patient had been receiving peritoneal dialysis as renal replacement therapy. The donor was a 16-year-old, 167 cm, 58.9 kg, white woman who had died of a motor vehicle accident. Her previous medical history was pristine. Immunosuppression consisted of antithymocyte globulin for induction therapy and tacrolimus, mycophenolate mofetil, and prednisone for maintenance therapy. The immediate post-operative course was uneventful, and the patient was discharged on postoperative day 7. Follow-up was complicated by immunosuppression-related toxicity causing de novo diabetes mellitus 20 days after the transplant and arterial hypertension. In addition, the patient became morbidly obese weighing 113 kg immediately after the transplant, and most recently weighing 143 kg in January 2012.

From 2006 to 2011, he did well and had normal kidney function. In February 2011, he presented with a rising serum creatinine. A renal biopsy was therefore done, showing plasma cell-rich acute cell-mediated tubulointerstitial rejection superimposed on advanced chronic allograft rejection most closely resembling Banff Ib rejection, in association with arteriolar hyalinosis; interlobular arteries were normal and free of intimal arteritis. Anti-thymocyte globulin and intravenous immunoglobulin were given. He had a mildly elevated intact parathyroid hormone at this time (108 pg/mL nL12-72) but a normal serum calcium. This is consistent with the assumption that heterotopic ossification is not associated with any metabolic condition.8 The patient was started on alemtuzumab when a follow-up biopsy done in March 2011 revealed that the acute rejection had not resolved. In November 2011, a renal biopsy revealed advanced chronic allograft nephropathy with focal segmental glomerulosclerosis and marked dense interstitial fibrosis associated with OM (Figures 1A and B). Additionally, plasma cell-rich acute cell-mediated tubulointerstitial rejection around atrophic tubules was still present. An ultrasound of the renal allograft showed multiple cortical echogenic foci that were not present in previous examinations. The most recent biopsy taken January 2012 did not reveal OM, likely owing to a zonation phenomenon. An ultrasound taken in November 2011 showed multiple peripheral cortical calcifications; we assumed that OM was missed owing to a sampling error.


Of the reported cases of OM in renal allografts, emerging similarities may be elucidated. Bataille hypothesized that chronic ischemia and inflammation are responsible for ossification of the renal allograft. Furthermore, a protracted period of renal injury is not required. The time between no evidence of heterotopic bone and discovery of osseous metaplasia is abrupt, ranging from 6 months to 2 years.3-7 The histology of each case of OM in a renal allograft is strikingly similar. Multiple case reports have described the histologic appearance as metaplastic foci of bone within fibrous tissue rich in fibroblasts and swathed by a lymphoid and plasma cell infiltrate.6,7 This suggests that pathologic conditions and mechanisms of OM formation in renal allografts are identical.

Three prerequisite components have been proposed in the pathogenesis of heteroplastic bone formation: osteogenic precursor cells, inducing factors, and a suitable environment.9 In 1920, Asami and Dock showed that OM occurs when renal vessels are ligated in the rabbit.10 They speculated that ischemic and inflammatory conditions recruit young fibroblasts into the renal tissue that accumulate and form a membrane that lays down bone. Subsequently, areas of scarring and hyalinosis adjacent to the ossified membranes are transformed into bone. Thus, while fibroblasts potentially represent osteogenic precursor cells and orchestrate the whole process of neo-osteogenesis, ischemia and inflammation may act as inducing factors, altogether forming a suitable environment for ossification.

In the rat myocardium, Delo showed that the amount of osseous formation positively correlated with the size of myocardial infarction.11 It can be inferred that the mechanism of osseous metaplasia is germane to any ischemic tissue with an environment favoring bone formation. McCarthy hypothesized that the induction signal is likely a protein secreted from cells of the injured tissue or from inflammatory cells arriving in response to the tissue injury.8 Specifically, Kaplan deduced that inflammatory prostaglandins and bone morphogenetic proteins are potent costimulatory molecules in the induction of heterotopic bone.12 As evidenced in the histologic specimens from our case, scarring and hyalinosis are widespread in the allograft potentially due to the inciting ischemia and inflammation. Dense areas of scar tissue may become secondarily ossified as seen in the renal biopsies from each case and as had already been described more than a century ago.13


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Volume : 12
Issue : 4
Pages : 371 - 373
DOI : 10.6002/ect.2013.0149

PDF VIEW [212] KB.

From the 1Wake Forest University School of Medicine, the 2Department of General Surgery, Section of Transplant; the 3Wake Forest Institute for Regenerative Medicine; and the 4Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
Acknowledgements: The authors of this manuscript have no conflicts of interest to disclose.
Corresponding author: Giuseppe Orlando, MD, PhD, MCF, Wake Forest University School of Medicine, Wake Forest Institute for Regenerative Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Phone: +1 336 716 6903
Fax: +1 336 713 5055