Successful Kidney Transplantation from Donor with Marfan's Syndrome
* Corresponding author: U. Huynh-Do, firstname.lastname@example.org
Marfan's syndrome is caused by mutations in the extracellular matrix protein fibrillin-1 with aortic aneurysm and dissection being its most life-threatening manifestations.
Kidney transplantation from donors with Marfan's syndrome has never been reported in the literature, possibly because of reticences due to the underlying connective tissue disease. Here, we report two patients with end-stage renal disease, transplanted with the kidneys from a donor with Marfan's syndrome who died of aortic dissection and cerebral hemorrhage. After delayed graft function in both recipients, renal function normalized with no renovascular complications and negative proteinuria for 6 years in one patient and 2 years in the other patient, who died from an ischemic cerebrovascular insult. Kidneys from organ donors with Marfan's syndrome might be suitable for transplantation.
Marfan's syndrome is a systemic disorder of connective tissue caused by mutations in the extracellular matrix protein fibrillin-1 showing pathologic changes in the skeletal, ocular and cardiovascular systems with aortic aneurysms representing the most life-threatening manifestation (1). Although the literature reports one successful case of renal autotransplantation to preserve renal function in an individual with Marfan's syndrome and dissection of the descending aorta (2), kidney transplantation (KTx) from donors with Marfan's syndrome has not been described previously. No statement whether kidneys from donors with Marfan's syndrome are suitable for transplantation are available from the U.S. (3) or European (4) guidelines for deceased organ donation.
Here, we discuss two patients with end-stage renal disease (ESRD) transplanted with the kidneys from a 47-year-old heart-beating donor who died of aortic dissection and cerebral hemorrhage because of Marfan's syndrome. Renal function of the donor was normal, proteinuria and serologic screening for hepatitis B, C and HIV were negative. The recipients were informed about the underlying disease state of the donor and the potential uncertainties.
The first kidney was transplanted to a 37-year-old male patient on chronic hemodialysis therapy due to rapid progressive glomerulonephritis with Goodpasture syndrome 2 years earlier. Cross-match was negative, two HLA identities (1A, 1DR) were present and cold ischemia time was 8 h. The postoperative course was complicated by delayed graft function requiring hemodialysis treatment for 2 weeks, thereafter renal function improved rapidly to a serum creatinine of 118 μmol/L and a creatinine clearance of 60 mL/min without proteinuria. Initial immunosuppression consisted of prednisone, cyclosporine A and basiliximab. Three months after KTx an acute interstitial rejection (Banff IIa) was diagnosed by renal biopsy. No structural abnormalities in both glomeruli and arteries of the graft were identified and anti-glomerular basement membrane (anti-GBM) staining was negative. Treatment with methylprednisolone and addition of rapamycin to the prednisone and cyclosporin A maintenance regimen resulted in rapid recovery of the renal function. Four years later, rapamycin was stopped because of chronic diarrhea and replaced by azathioprine (1.2 mg/kg BW). Six years after transplantation, renal function is stable with a creatinine clearance of 50 mL/min and negative proteinuria. Sonographic examination of the graft vessel reveals no abnormalities.
The second kidney from the same donor was transplanted to a 53-year-old male patient with ESRD suffering from autosomal dominant polycystic kidney disease, diabetes mellitus and arterial hypertension. The patient had a history of cerebrovascular insult without neurological deficits. Cross-match was negative and three HLA compatibility were present (1A, 1B, 1 DR). Cold ischemia time was 10 h. After delayed graft function, not requiring dialysis and attributed to intraoperative hypotension, renal function improved. The same initial immunosuppressive therapy was used as in patient 1 (prednisone, cyclosporine A and basiliximab). Three weeks after KTx serum creatinine was 100 μM/L with a creatinine clearance of 70 mL/min and absence of proteinuria. Six months after KTx the immunosuppressive therapy was switched to a steroid-free regimen with azathioprine (1.2 mg/kg BW) and cyclosporine A. Renal function remained stable (creatinine clearance 70 mL/min) and proteinuria was negative for 2 years after KTx when the patient died because of a new, ischemic cerebrovascular insult.
The majority of potential deceased organ donors are not ‘ideal kidney donors’. The decision to accept or refuse an organ for transplantation is a challenge for transplant physicians. The shortage of kidney donors implies a need for these limits of acceptance to be widened. Organs from patients with Marfan's syndrome represent such a challenge.
Marfan's syndrome is a rare autosomal dominant condition with an estimated incidence of 2–3 per 10 000 individuals (1). Individuals affected are at risk for cerebral hemorrhage, cerebral ischemia (5) and aortic aneurysms (1) and are therefore rare, but potential deceased kidney donors. To date no report discussing the successful use of these organs has appeared in the literature. The two patients presented here received their kidneys from a donor who died of aortic dissection as a complication of Marfan's syndrome. Initially, delayed graft function was present in both recipients, but resolved rapidly and excellent renal allograft function without proteinuria was encountered during the entire observation time up to 6 years.
Only limited data exist about renal involvement in Marfan's syndrome. Some authors describe microhematuria and proteinuria associated with ultrastructural GBM alterations and characteristic vascular alterations with disruption of the internal elastic lamina in some cases (6,7). The renal phenotype has been analyzed in fibrillin-underexpressing mice, an animal model for Marfan's syndrome (8). Functional deficiencies of the glomerulus were absent in these mice and alterations in renal histology were only subtle with a reduced glomerular volume and mesangial area probably due to a reduced mesangial cell volume. Positive immunoreaction of fibrillin-1 was detected in the tubulointerstitium, perivascular areas and glomerular mesangium of the wild-type mice (8). Taken together these observations in humans and in mutant mice suggest that Marfan's syndrome should not have a major deleterious effect on renal function, a hypothesis compatible with the good long-term renal function and absence of proteinuria observed in both our patients.
Patients with Marfan's syndrome are at risk for vascular dissection and intimal tears usually presenting more insidiously than acute dissection of the vessel wall (1). This is related directly to the mutation of fibrillin-1, and their continued deposition is absolutely required for the maturation and function of the vessels during neonatal life (9). The possibility of developing vascular complications in the graft vessels such as dilatation, dissection and intimal tears remains a concern in the graft kidney from a donor with Marfan's syndrome, because there is evidence that fibrillin-1 is released by autochtonous cells from the blood vessels, i.e. mainly from vascular smooth muscle cells (9). In front of this concern, we performed routine control of the KTx with vascular Doppler ultrasound in our two patients. So far, no abnormality has been detected during the 2 years observation period in patient 2 and the 6 years in patient 1. In patient 1 routine observation of potential vascular complications is still ongoing.
Another hypothetical complication deserves discussion: Do patients transplanted with an organ from a donor with Marfan's syndrome develop antibodies against mutated fibrillin-1? This question cannot be answered with the present observation. However, the absence of anti-GBM staining in the graft biopsy in patient 1 and the excellent middle- to long-term graft survival in both patients are arguments against a potential deleterious effect of such antibodies, even if present. Nevertheless, caution is a good advice in the light of the knowledge about Alport's syndrome. About 10–20% of patients suffering from this disease develop anti-GBM antibodies in response to the α chain of type IV collagen, which represents for them a neoantigen after having received a genetically ‘normal’ kidney (10). Fortunately, most commonly the IgG deposition along the GBM does not have any effect on allograft function. However, a small fraction, possibly as few as 5% of Alport patients develop immunization leading to a crescentic glomerulonephritis (10). Therefore, in our surviving patient, regular screening for proteinuria or microhematuria is still ongoing, and has remained negative to date.
In conclusion, the experience of the two patients presented here suggests that kidneys from organ donors with Marfan's syndrome are suitable for transplantation. Careful monitoring is, however, recommended because of the potential risk of developing vascular complications in both large and small graft vessels and the potential immunogenic role of the mutated fibrillin-1 protein in the transplanted kidney.
This work was supported by a grant from the Swiss National Foundation for Scientific Research 3100A0-10'5871 to U. Huynh-Do.