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To the Editor:

On March 2004, a 30-year-old male received a kidney graft from a 19-year-old lady dead from a brain trauma complicated by massive gastrointestinal bleeding and nonoliguric acute kidney injury associated with moderate thrombocytopenia, increased serum lactate dehydrogenase levels and slightly prolonged international normalized ratio.

Surgery was uneventful, but kidney function did not recover. A pretransplant graft biopsy sample processed shortly after surgery showed acute tubular necrosis with microvascular thrombosis (Figure 1A and B). Despite unfractionated heparin infusion, serum creatinine levels did not improve. On day 6, a second transplant biopsy again showed fresh microthrombi in approximately 30% of glomeruli, without signs of rejection (Figure 1C and D). One hundred milligrams of recombinant tissue plasminogen activator were infused, followed by subcutaneous injection of 100 U/kg of enoxaparin twice daily. After a transient improvement in kidney perfusion and function, serum creatinine progressively increased and the patient resumed hemodialysis in July 2006. The explanted graft disclosed chronic allograft nephropathy. A subsequent deceased-donor transplant was uneventful.

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Figure 1. Light microscopic findings in graft biopsies. Pretransplant. (A) Periodic acid-Schiff stain: severe preglomerular arteriolar thrombosis and massive tubular necrosis. (B) Masson's trichrome stain: thrombotic occlusion of a small renal artery, glomerular capillary thrombosis and focal tubular necrosis. Magnification: (A) ×300, (B) ×600. Posttransplant day 6. (C) Periodic acid-Schiff stain: preglomerular arteriolar thrombosis and moderate tubular dilatation with epithelial flattening. (D) Masson's trichrome stain: preglomerular and intraglomerular thrombosis, tubular epithelial degeneration, focal tubular vacuolization and dilatation with intraluminal cell debris and moderate interstitial edema. Magnification: (C) and (D) ×300.

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Several years later, sequencing DNA from the first donor for genes coding circulating (C3 and Factors H, B and I) and cell-bound (membrane cofactor protein and thrombomodulin) complement regulators revealed a heterozygous missense mutation in the thrombomodulin gene causing the p.V81I change in the N-terminal lectin-like (D1) domain.

Diffuse microthrombi in renal grafts from brain-trauma donors are normally observed in a context of disseminated intravascular coagulation, and usually reabsorb early posttransplant in parallel with renal function recovery [1]. Conceivably, the unexpected outcome of our patient was likely explained by the mutated donor thrombomodulin that sustained kidney thrombi formation even posttransplant. Thrombomodulin is a transmembrane glycoprotein expressed on endothelial surfaces and organized into five domains that exhibit various anti-coagulant and anti-inflammatory properties [2]. In particular, the D1 domain, housing the V81I change found in our patient, is directly involved in complement system inhibition through factor I–mediated C3b inactivation [2]. D1 heterozygous mutations have been recently identified in 2% of atypical hemolytic-uremic syndrome (aHUS) cases, mostly children with viral prodromes, and the 81I variant has a severely impaired protective effect on CHO-K1 cell surface from activated complement [3]. Thus, defective thrombomodulin activity might have predisposed our donor to microangiopathic disease upon brain trauma–induced systemic complement activation. Proteolytic cleavage of endothelial thrombomodulin [4] might have contributed to further reduce its activity and high-dose norepinephrine infusion, required to sustain donor blood pressure, might have concurred to fuel the microangiopathic process through direct endothelial damage and platelet activation. The fact that the thrombomodulin defect was restricted to the graft may also explain why, despite severe and irreversible renal microangiopathy, systemic signs of HUS were subtle in the recipient. On the other hand, the predisposing role, if any, of possible complement abnormalities in the recipient—sometimes associated with IgA nephropathy [5]—was most likely marginal, since a second transplant from a donor without evidence of thrombotic microangiopathy was uneventful.

Thus, we suggest that trauma-induced complement activation might have precipitated aHUS in a donor predisposed to the disease because of a thrombomodulin defect and, posttransplant, defective thrombomodulin might have sustained the microangiopathic process in the graft. Thrombolytic therapy appeared to stifle the disease, but could not prevent subsequent relentless exhaustion of residual nephrons surviving acute microangiopathy.

Acknowledgments

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  2. Acknowledgments
  3. Disclosure
  4. References

We thank Eliana Gotti and the Nephrology Unit staff for patient care and monitoring. Mauro Abbate and Camillo Carrara helped prepare the iconographic material and Manuela Passera the manuscript. RP is a recipient of a research contract from Progetto DDD Onlus, Associazione per la lotta alla DDD. This study was partially supported by Fondazione ART per la Ricerca sui Trapianti (Milan, Italy).

  • F. Mescia1, R. Piras2, M. Noris2, G. Marchetti1, G. Rossini3, G. Remuzzi1,2,* and P. Ruggenenti1,2

  • 1Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy

  • 2IRCCS—Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases “Aldo e Cele Daccò”, Bergamo, Italy

  • 3Centro Interregionale di Riferimento del Nord Italia Transplant, IRCCS—Ospedale Maggiore Policlinico, Milan, Italy

  • *Corresponding author: Giuseppe Remuzzi, giuseppe.remuzzi@marionegri.it

Disclosure

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  2. Acknowledgments
  3. Disclosure
  4. References

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

References

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  2. Acknowledgments
  3. Disclosure
  4. References
  • 1
    Pastural M, Barrou B, Delcourt A, Bitker MO, Ourahma S, Richard F. Successful kidney transplantation using organs from a donor with disseminated intravascular coagulation and impaired renal function: Case report and review of the literature. Nephrol Dial Transplant 2001; 16: 412415.
  • 2
    Martin FA, Murphy RP, Cummins PM. Thrombomodulin and the vascular endothelium: Insights into functional, regulatory, and therapeutic aspects. Am J Physiol Heart Circ Physiol 2013; 304: H1585H1597.
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    Delvaeye M, Noris M, De Vriese A, et al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med 2009; 361: 345357.
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    Boldt J, Wollbruck T, Sonneborn S, Welters A, Hempelmann G. Thrombomodulin in intensive care patients. Intensive Care Med 1995; 21: 645650.
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    Schmitt R, Krmar RT, Kristoffersson A, Söderberg M, Karpman D. IgA nephropathy associated with a novel N-terminal mutation in factor H. Eur J Pediatr 2011; 170: 107110.